Aprepitant for the Prevention of Acute Chemotherapy- Induced Nausea and Vomiting in Children: Overcoming Barriers

Priya Patel

A thesis submitted in conformity with the requirements for the degree of Master of Science Department of Pharmaceutical Sciences University of Toronto

Aprepitant for the Prevention of Acute Chemotherapy-Induced Nausea and Vomiting in Children: Overcoming Barriers

Priya Patel

Master of Science

Department of Pharmaceutical Sciences University of Toronto

2018 Abstract

Aprepitant is an effective antiemetic for the prevention of acute chemotherapy-induced nausea and vomiting (CINV) in children. This thesis presents an updated clinical practice guideline for the prevention of acute CINV that recommends children receiving highly emetogenic chemotherapy be given an antiemetic regimen that includes aprepitant. However, aprepitant- antineoplastic drug interactions and lack of a commercially available aprepitant oral liquid formulation limit its utility. A systematic review of aprepitant-drug interactions was undertaken to identify clinically significant interactions. Significant pharmacokinetic interactions were found between aprepitant and the following antineoplastic agents: bosutinib, cabazitaxel and cyclophosphamide. A crossover study was conducted in healthy adult volunteers to establish the relative bioavailability of an extemporaneous aprepitant oral suspension compared to the commercially available capsule. Relative bioavailability of the oral suspension was found to be

82.3%, demonstrating sufficient absorption of aprepitant to have an antiemetic effect. Overall, these projects have addressed barriers to aprepitant use in children.

Acknowledgments

I would like to begin by thanking my supervisor, Dr. L. Lee Dupuis, for her ongoing guidance and support with the completion of my Masters requirements as well as my Pharmacy Practice Residency. I extend my sincerest gratitude to her for the numerous opportunities she has provided me for learning and professional growth over the past three years. It has truly been my honour to have had the opportunity to work with Lee and her team.

I also would like to acknowledge the members of my thesis committee: Dr. Micheline Piquette- Miller, Dr. Beth Sproule, and Mr. Scott Walker. I appreciate all of the questions they asked and insightful feedback they gave as it has helped me become a better scientist.

As well, the publications included in this thesis would not have been possible without the contributions of my co-authors: L. Lee Dupuis, Paula D. Robinson, Jennifer Thackray, Jacqueline Flank, Mark T. Holdsworth, Paul Gibson, Andrea Orsey, Carol Portwine, Jason Freedman, Jennifer R. Madden, Robert Phillips, Lillian Sung, Micheline Piquette-Miller, J. Steven Leeder, Scott Walker, Paul Nathan, Jocelyne Volpe and Sue Zupanec.

I would also like to thank the Pediatric Oncology Group of Ontario for their generous financial support provided to me with the Clinician Scholar Award – Research Fellowship for 2017-2018, as well as the University of Toronto’s Pharmaceutical Sciences Graduate Department for their departmental funding support from 2015-2016. The Relative Bioavailability of an Extemporaneous Oral Suspension of Aprepitant in Healthy Adult Volunteers study would also not have been possible without the generous financial support from the Garron Family Cancer Centre and the Pediatric Oncology Group of Ontario.

Moreover, I would also like to acknowledge The Hospital for Sick Children’s Department of Pharmacy, and most especially all of my preceptors who provided their ongoing support and feedback for my Masters research during my Pharmacy Practice Residency.

Finally, I would like to thank my friends and family for their unconditional love and support as I pursued this degree. Without them, I could not have accomplished all that I have thus far in my career.

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Table of Contents

Acknowledgments...... iii

List of Tables ...... ix

List of Figures ...... xiii

List of Abbreviations ...... xvi

List of Appendices ...... xviii

Chapter 1 Introduction ...... 1

1.1 Chemotherapy-induced Nausea and Vomiting ...... 1

1.1.1 CINV Classification ...... 1

1.1.2 Pathophysiology of CINV...... 2

1.1.3 Emetogenicity Classification ...... 4

1.2 Prevention of Acute Chemotherapy-Induced Nausea and Vomiting in Children...... 4

1.3 Aprepitant ...... 7

1.3.1 Mechanism of Action ...... 7

1.3.2 Pharmacokinetics ...... 7

1.3.3 Pharmacokinetic-Pharmacodynamic Relationship ...... 10

1.3.4 Adult Experience ...... 12

1.3.5 Pediatric Experience ...... 12

1.3.6 Aprepitant Safety ...... 13

1.3.7 Aprepitant-Drug Interactions ...... 14

1.4 Project Rationale and Purpose of Studies ...... 16

1.5 References ...... 18

Chapter 2 Guideline for the Prevention of Acute Chemotherapy-Induced Nausea and Vomiting in Pediatric Cancer Patients: A Focused Update ...... 24

2.1 Abstract ...... 25

2.2 Introduction ...... 25 iv

2.3 Methods...... 26

2.3.1 Guideline panel and health questions addressed ...... 26

2.3.2 Evidence identification and review ...... 26

2.3.3 External review ...... 27

2.3.4 Guideline updates...... 27

2.4 Results ...... 27

2.4.1 Health Question #1: What pharmacological interventions provide optimal control of acute CINV in children receiving highly emetogenic chemotherapy (HEC)? ...... 29

2.4.2 Health Question #2: What pharmacological interventions provide optimal control of acute CINV in children receiving moderately emetogenic chemotherapy (MEC)? ...... 33

2.4.3 Health Question #3: What doses of aprepitant and palonosetron are known to be effective in children receiving chemotherapy? ...... 36

2.4.4 Implementation Considerations ...... 39

2.5 Conclusions ...... 39

2.6 Acknowledgments...... 39

2.7 References ...... 46

Chapter 3 Drug Interactions with Aprepitant and Fosaprepitant: A Systematic Review ...... 51

3.1 Abstract ...... 52

3.2 Introduction ...... 52

3.3 Methods...... 53

3.4 Results ...... 54

3.4.1 Publication selection ...... 54

3.4.2 Publication characteristics ...... 54

3.4.3 Pharmacokinetic interactions with aprepitant or fosaprepitant ...... 55

3.4.4 Adverse events ascribed to interactions with aprepitant or fosaprepitant ...... 56

3.5 Discussion ...... 59

3.6 Conclusion ...... 62

3.7 Acknowledgements ...... 62

3.8 References ...... 70

Chapter 4 Relative Bioavailability of an Extemporaneous Oral Suspension of Aprepitant in Healthy Adult Volunteers ...... 77

4.1 Abstract ...... 78

4.2 Introduction ...... 78

4.3 Materials and Methods ...... 80

4.3.1 Eligibility ...... 80

4.3.2 Aprepitant Dosing ...... 81

4.3.3 Aprepitant Blood Sample Collection ...... 81

4.3.4 Adverse Event Monitoring ...... 81

4.3.5 Aprepitant Plasma Concentration Determination ...... 82

4.3.6 Pharmacokinetic Analysis ...... 82

4.3.7 Statistical Considerations ...... 84

4.4 Results ...... 86

4.4.1 Volunteer Demographics and Adverse Events ...... 86

4.4.2 Pharmacokinetic Parameters ...... 86

4.4.3 Relative Bioavailability and Bioequivalence Determination ...... 87

4.4.4 First Order, One Compartment Model Results ...... 88

4.5 Discussion ...... 88

4.6 Acknowledgments...... 91

4.7 References ...... 99

Chapter 5 Discussion and Conclusions ...... 102

5.1 Summary of Key Findings ...... 102

5.2 Strengths and Limitations ...... 103

5.3 Future Research ...... 104

5.4 Conclusions ...... 105

5.5 References ...... 106

Appendices ...... 108

Appendix A. Supplementary Material for Chapter 2: Guideline for the Prevention of Acute Chemotherapy-Induced Nausea and Vomiting in Pediatric Cancer Patients: A Focused Update ...... 108

A. Guideline Panel Members ...... 108

B. Systematic review of primary studies evaluating aprepitant and palonosetron for acute CINV prophylaxis in children ...... 110

C. Systematic review of meta-analyses evaluating palonosetron vs other 5HT3- antagonists for acute CINV prophylaxis ...... 125

D. Systematic review of palonosetron pharmacokinetic studies ...... 131

E. Pediatric Palonosetron Dosing and Pharmacokinetics ...... 166

F. External Content Review of Draft Guideline ...... 167

G. Health Questions, Summary of Recommendations and Remarks for the Prevention of Acute Chemotherapy-Induced Nausea and Vomiting in Children ...... 170

H. References ...... 174

Appendix B. Supplementary Material for Chapter 3: Aprepitant and Fosaprepitant Drug Interactions: A Systematic Review ...... 178

A. Literature Search ...... 178

B. Publication Selection, Data Extraction and Quality Assessment Procedures ...... 179

C. Study Results ...... 181

D. Victim Drug Routes of Metabolism, Transporters where Victim Drugs are Substrates and Renal Elimination ...... 241

E. References ...... 243

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Appendix C. Supplementary Material for Chapter 4: Relative Bioavailability of an Extemporaneous Oral Suspension of Aprepitant in Healthy Adult Volunteers ...... 250

A. Aprepitant Oral Suspension Compounding Formulation ...... 250

B. Extemporaneous Aprepitant Oral Suspension Data vs Historical Aprepitant Capsule Data ...... 250

C. Individual Study Volunteer Data...... 251

D. Exploratory Analysis...... 270

E. References ...... 272

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List of Tables

Chapter 1. Introduction

Table 1.1 Chemotherapy emetogenicity classification ...... 4

Table 1.2 Summary of recommendations made by three clinical practice guidelines for the prevention of acute CINV in children ...... 6

Table 1.3 Summary of aprepitant pharmacokinetic data in children and adults ...... 10

Chapter 2. Guideline for the Prevention of Acute Chemotherapy-Induced Nausea and Vomiting in Pediatric Cancer Patients: A Focused Update

Table 2.1 Health questions and summary of recommendations for the prevention of acute chemotherapy-induced nausea and vomiting in pediatric cancer patients ...... 40

Table 2.2 Summary of included studies evaluating aprepitant ...... 42

Table 2.3 Summary of included studies evaluating palonosetron ...... 43

Table 2.4 Aprepitant and palonosetron for the prevention of acute chemotherapy-induced nausea and vomiting: examples of evidence gaps ...... 44

Chapter 3. Drug Interactions with Aprepitant and Fosaprepitant: A Systematic Review

Table 3.1 Study characteristics of included studies ...... 63

Table 3.2 Summary of findings regarding pharmacokinetic interactions with aprepitant/fosaprepitant...... 68

Chapter 4. Relative Bioavailability of an Extemporaneous Oral Suspension of Aprepitant in Healthy Adult Volunteers

Table 4.1 Baseline demographics of study volunteers...... 92

Table 4.2 Summary of adverse events ...... 92

Table 4.3 Arithmetic mean pharmacokinetic parameters for aprepitant from noncompartmental analysis and first order, one compartment model analysis ...... 92

Table 4.4 Noncompartmental analysis-derived parameter estimates for each subject given an aprepitant 125 mg capsule ...... 93

Table 4.5 Noncompartmental analysis-derived parameter estimates for each subject given aprepitant 125 mg as the extemporaneous oral suspension ...... 94

Table 4.6 First order, one compartment derived parameter estimates for each subject given aprepitant capsule...... 94 ix

Table 4.7 First order, one compartment derived parameter estimates for each subject given aprepitant suspension ...... 95

Table 4.8 Summary of p-values for treatment, period, sequence effects for the pharmacokinetic parameters of aprepitant ...... 95

Table 4.9 Geometric least mean squares ratio, 90% confidence intervals and variance estimates of pharmacokinetic parameters for aprepitant oral suspension versus oral capsule ...... 96

Appendix A. Supplementary Material for Chapter 2: Guideline for the Prevention of Acute Chemotherapy-Induced Nausea and Vomiting in Pediatric Cancer Patients: A Focused Update

Supplementary Table A1 Search Strategies: Systematic review of primary studies evaluating aprepitant and palonosetron for acute CINV prophylaxis in children ...... 112

Supplementary Table A2 Summary of studies used to inform recommendations 1.1-1.6: highly emetogenic antineoplastic therapy as ranked by POGO Guideline for Classification of the Acute Emetogenic Potential of Antineoplastic Medication in Pediatric Cancer Patients ...... 115

Supplementary Table A3 Summary of studies used to inform recommendations 1.1-1.6: highly emetogenic antineoplastic therapy as ranked by study investigators where insufficient information available to assign emetogenic risk using the POGO Guideline for Classification of the Acute Emetogenic Potential of Antineoplastic Medication in Pediatric Cancer Patients .... 116

Supplementary Table A4 Summary of studies used to inform recommendations 2.1-2.4: moderately emetogenic antineoplastic therapy as ranked by POGO Guideline for Classification of the Acute Emetogenic Potential of Antineoplastic Medication in Pediatric Cancer Patients 118

Supplementary Table A5 Summary of studies used to inform recommendations 2.1-2.4: moderately emetogenic antineoplastic therapy as ranked by study investigators where insufficient information available to assign emetogenic risk using the POGO Guideline for Classification of the Acute Emetogenic Potential of Antineoplastic Medication in Pediatric Cancer Patients .... 119

Supplementary Table A6 Clinical adverse events reported in randomized controlled trials evaluating aprepitant for CINV prophylaxis in children ...... 122

Supplementary Table A7 Clinical adverse events in randomized controlled trials evaluating palonosetron for CINV prophylaxis in children ...... 123

Supplementary Table A8 Risk of bias for randomized controlled trials ...... 124

Supplementary Table A9 Search Strategies: systematic review of meta-analyses evaluating palonosetron vs other 5HT3-antagonists for acute CINV prophylaxis ...... 127

Supplementary Table A10 Summary of findings of systematic search for meta-analyses evaluating palonosetron vs other 5-HT3 antagonists ...... 130

Supplementary Table A11 Search strategies: systematic review of palonosetron pharmacokinetic studies ...... 133

Supplementary Table A12 Summary of findings from systematic search of palonosetron pharmacokinetics ...... 136

Supplementary Table A13 Palonosetron pharmacokinetic information provided in European Medicines Agency palonosetron approval document ...... 166

Supplementary Table A14 Summary of palonosetron dosing from available pediatric Data ... 166

Supplementary Table A15 Expert content reviewers’ agreement with survey statements ...... 167

Supplementary Table A16 Comments of external content reviewers and panel responses ...... 167

Supplementary Table A17 Health questions, summary of recommendations and remarks for the prevention of acute chemotherapy-induced nausea and vomiting in children ...... 170

Appendix B. Supplementary Material for Chapter 3: Aprepitant and Fosaprepitant Drug Interactions: A Systematic Review

Supplementary Table B1 Search strategy ...... 178

Supplementary Table B2 List of grey literature sources searched ...... 179

Supplementary Table B3 Downs and Black quality assessment for publications evaluating pharmacokinetic drug interactions between aprepitant or fosaprepitant and antineoplastic drugs ...... 181

Supplementary Table B4 Downs and Black quality assessment for publications evaluating clinical drug interactions between aprepitant or fosaprepitant and non-antineoplastic drugs ... 184

Supplementary Table B5 Downs and Black quality assessment for publications evaluating clinical drug interactions between aprepitant or fosaprepitant and antineoplastic and non- antineoplastic drugs ...... 186

Supplementary Table B6 Studies evaluating pharamcokinetic drug interactions between aprepitant or fosaprepitant and antineoplastic drugs ...... 189

Supplementary Table B7 Studies evaluating pharamcokinetic drug interactions between aprepitant or fosaprepitant and non-antineoplastic drugs ...... 200

Supplementary Table B8 Drug interaction studies evaluating potential adverse events resulting from potential drug interactions between aprepitant or fosaprepitant and an antineoplastic agent ...... 221

Supplementary Table B9 Drug interaction studies evaluating potential adverse events resulting from potential drug interactions between aprepitant or fosaprepitant and a non-antineoplastic agent ...... 231

Supplementary Table B10 Drug interaction probability scale evaluation for case reports ...... 238

Appendix C. Supplementary Material for Chapter 4: Relative Bioavailability of an Extemporeneous Oral Suspension of Aprepitant in Healthy Adult Volunteers

Supplementary Table C1 Comparison of the extemporaneous oral aprepitant suspension data to the historical aprepitant capsule data ...... 250

Supplementary Table C2 Aprepitant plasma concentrations (ng/mL) for each study volunteer after administration of an aprepitant 125 mg capsule ...... 251

Supplementary Table C3 Aprepitant plasma concentrations (ng/mL) for each study volunteer after administration of aprepitant 125 mg as the extemporaneous oral suspension ...... 252

Supplementary Table C4 Geometric least mean squares ratio, 90% confidence intervals and variance estimates of pharmacokinetic parameters for aprepitant oral suspension versus oral capsule excluding APREP1 ...... 271

Supplementary Table C5 Geometric least mean squares ratio, 90% confidence intervals and variance estimates of pharmacokinetic parameters for aprepitant oral suspension versus oral capsule excluding APREP13 ...... 271

Supplementary Table C6 Geometric least mean squares ratio, 90% confidence intervals and variance estimates of pharmacokinetic parameters for aprepitant oral suspension versus oral capsule excluding APREP14 ...... 272

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List of Figures

Chapter 1. Introduction

Figure 1.1 Pathways by which chemotherapeutic agents may produce an emetic response ...... 3

Figure 1.2 NK1 receptor occupancy with various aprepitant dosing regimens ...... 11

Chapter 2. Guideline for the Prevention of Acute Chemotherapy-Induced Nausea and Vomiting in Pediatric Cancer Patients: A Focused Update

Figure 2.1 Summary of recommendations regarding antiemetic agent selection for prevention of acute CINV in children ...... 45

Chapter 3. Drug Interactions with Aprepitant and Fosaprepitant: A Systematic Review

Figure 3.1 Study Identification Flow Diagram ...... 69

Chapter 4. Relative Bioavailability of an Extemporaneous Oral Suspension of Aprepitant in Healthy Adult Volunteers

Figure 4.1 Average aprepitant concentration versus time profile for all 17 study volunteers for the apreptiant oral capsule and oral suspension ...... 97

Figure 4.2a Slope plot comparing study volunteers’ AUC0-48h with the aprepitant capsule versus the oral suspension ...... 98

Figure 4.2b Slope plot comparing study volunteers’ AUC0-inf with the aprepitant capsule versus the oral suspension ...... 98

Figure 4.2c Slope plot comparing study volunteers’ Cmax with the aprepitant capsule versus the oral suspension ...... 98

Appendix A. Supplementary Material for Chapter 2: Guideline for the Prevention of Acute Chemotherapy-Induced Nausea and Vomiting in Pediatric Cancer Patients: A Focused Update

Supplementary Figure A1 PRISMA flowchart for the systematic review of primary studies evaluating aprepitant and palonosetron for acute CINV prophylaxis in children ...... 111

Supplementary Figure A2 PRISMA flowchart for the systematic reviewof meta-analyses evaluating palonosetron vs other 5HT3-antagonists for acute CINV prophylaxis ...... 126

Supplementary Figure A3 PRISMA flowchart for the systematic review of palonosetron pharmacokinetics ...... 132

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Appendix C. Supplementary Material for Chapter 4: Relative Bioavailability of an Extemporaneous Oral Suspension of Aprepitant in Healthy Adult Volunteers

Supplementary Figure C1a Aprepitant concentration versus time plot for APREP1 ...... 253

Supplementary Figure C1b Ln(aprepitant concentration) versus time plot for APREP1 ...... 253

Supplementary Figure C2a Aprepitant concentration versus time plot for APREP2 ...... 254

Supplementary Figure C2b Ln(aprepitant concentration) versus time plot for APREP2 ...... 254

Supplementary Figure C3a Aprepitant concentration versus time plot for APREP3 ...... 255

Supplementary Figure C3b Ln(aprepitant concentration) versus time plot for APREP3 ...... 255

Supplementary Figure C4a Aprepitant concentration versus time plot for APREP4 ...... 256

Supplementary Figure C4b Ln(aprepitant concentration) versus time plot for APREP4 ...... 256

Supplementary Figure C5a Aprepitant concentration versus time plot for APREP5 ...... 257

Supplementary Figure C5b Ln(aprepitant concentration) versus time plot for APREP5 ...... 257

Supplementary Figure C6a Aprepitant concentration versus time plot for APREP6 ...... 258

Supplementary Figure C6b Ln(aprepitant concentration) versus time plot for APREP6 ...... 258

Supplementary Figure C7a Aprepitant concentration versus time plot for APREP7 ...... 259

Supplementary Figure C7b Ln(aprepitant concentration) versus time plot for APREP7 ...... 259

Supplementary Figure C8a Aprepitant concentration versus time plot for APREP8 ...... 260

Supplementary Figure C8b Ln(aprepitant concentration) versus time plot for APREP8 ...... 260

Supplementary Figure C9a Aprepitant concentration versus time plot for APREP9 ...... 261

Supplementary Figure C9b Ln(aprepitant concentration) versus time plot for APREP9 ...... 261

Supplementary Figure C10a Aprepitant concentration versus time plot for APREP10 ...... 262

Supplementary Figure C10b Ln(aprepitant concentration) versus time plot for APREP10 ...... 262

Supplementary Figure C11a Aprepitant concentration versus time plot for APREP11 ...... 263

Supplementary Figure C11b Ln(aprepitant concentration) versus time plot for APREP11 ...... 263

Supplementary Figure C12a Aprepitant concentration versus time plot for APREP12 ...... 264

Supplementary Figure C12b Ln(aprepitant concentration) versus time plot for APREP12 ...... 264

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Supplementary Figure C13a Aprepitant concentration versus time plot for APREP13 ...... 265

Supplementary Figure C13b Ln(aprepitant concentration) versus time plot for APREP13 ...... 265

Supplementary Figure C14a Aprepitant concentration versus time plot for APREP14 ...... 266

Supplementary Figure C14b Ln(aprepitant concentration) versus time plot for APREP14 ...... 266

Supplementary Figure C15a Aprepitant concentration versus time plot for APREP15 ...... 267

Supplementary Figure C15b Ln(aprepitant concentration) versus time plot for APREP15 ...... 267

Supplementary Figure C16a Aprepitant concentration versus time plot for APREP16 ...... 268

Supplementary Figure C16b Ln(aprepitant concentration) versus time plot for APREP16 ...... 268

Supplementary Figure C17a Aprepitant concentration versus time plot for APREP17 ...... 269

Supplementary Figure C17b Ln(aprepitant concentration) versus time plot for APREP17 ...... 269

Supplementary Figure C18 Arithmetic mean ratio of the aprepitant suspension versus the capsule for area under the curve from time zero to 48 hours post aprepitant dose for all 17 study volunteers ...... 270

List of Abbreviations

5-HT3 5-hydroxytryptamine 3 ANOVA analysis of variance ASCO American Society of Clinical Oncology AUC area under the plasma concentration vs. time profile AUC0-24h area under the plasma concentration vs. time profile from zero to 24 hours AUC0-48h area under the plasma concentration vs. time profile from zero to 48 hours AUC0-inf area under the plasma concentration vs. time profile from zero to infinity CI confidence interval CINV chemotherapy-induced nausea and vomiting CIV chemotherapy-induced vomiting Cmax maximum concentration CTCAE Common Terminology Criteria for Adverse Events CV% coefficient of variation CYP cytochrome P450 DIPS Drug Interaction Probability Scale EMA European Medicines Agency ESMO European Society for Medical Oncology FDA United States Food and Drug Administration Geo-LS geometric least squares GI gastrointestinal GMR geometric mean ratio GRADE Grading of Recommendations Assessment, Development and Evaluation HEC highly emetogenic chemotherapy INR international normalized ratio IQR interquartile range IV Intravenous ke elimination rate constant LEC low emetogenic chemotherapy LQCT lowest quantifiable concentration time MASCC Multinational Association of Supportive Care in Cancer MEC moderately emetogenic chemotherapy NCA noncompartmental pharmacokinetic analysis NCI-CTC v3.0 National Cancer Insitute-Common Toxicity Criteria version 3.0 NK1 neurokinin-1 NR not reported PO per os (administered by mouth) PET positron emission tomography POGO Pediatric Oncology Group of Ontario PK pharmacokinetic PRISMA Preferred Items for Systematic Review and Meta-Analyses RCT randomized control trial RR relative risk SD standard deviation SickKids The Hospital for Sick Children SSRI selective serotonin reuptake inhibitor

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SNRI serotonin-norepinephrine reuptake inhibitor t1/2 half-life TLIN time point for where log-linear elimination begins Tmax time to maximum concentration VHEC very highly emetogenic chemotherapy

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List of Appendices

Appendix A. Supplementary Material for Chapter 2: Guideline for the Prevention of Acute Chemotherapy-Induced Nausea and Vomiting in Pediatric Cancer Patients: A Focused Update ...... 108

Appendix B. Supplementary Material for Chapter 3: Aprepitant and Fosaprepitant Drug Interactions: A Systematic Review ...... 178

Appendix C. Supplementary Material for Chapter 4: Relative Bioavailability of an Extemporaneous Oral Suspension of Aprepitant in Healthy Adult Volunteers ...... 250

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Chapter 1 Introduction

1.1 Chemotherapy-induced Nausea and Vomiting

Antiemetic therapies have improved in recent years, but chemotherapy-induced nausea and vomiting (CINV) are still common and among the most feared and distressing side effects of chemotherapy.1-4 A survey conducted at Ontario centres showed that parents identify nausea as the fourth most prevalent and bothersome treatment-related symptom experienced by their children.1 There are significant complications that may prove to be life-threatening as a result of poorly controlled CINV including dehydration, electrolyte imbalance, and Mallory-Weiss tears of the esophagus.5 Uncontrolled CINV has the potential to negatively impact a child’s quality of life as well as their family’s,1 and can lead to patients refusing to continue with their chemotherapy or hinder adherence to oral chemotherapy regimens.6, 7

Complete control of CINV, defined as no vomiting, no retching, no nausea, and no use of antiemetic agents other than those given for CINV prevention and no nausea-related change in usual appetite and diet,8 is the goal for all patients receiving chemotherapy.

1.1.1 CINV Classification

CINV can be classified as acute, delayed, anticipatory or breakthrough, based on the time at which the nausea, vomiting or retching occurs relative to when the chemotherapy is administered.5 It is important to distinguish between these subclasses as the mechanism by which each occurs differs and hence, the approach to prevention or control of each also varies. Acute CINV is defined as nausea, vomiting or retching that occurs within the first 24 hours following chemotherapy administration. Delayed CINV is nausea, vomiting or retching that occurs more than 24 hours after chemotherapy administration and can last for up to 96 hours.9 Anticipatory CINV refers to nausea, vomiting or retching that occurs within 24 hours prior to chemotherapy administration. Breakthrough CINV is defined as nausea, vomiting or retching that occurs during the acute or delayed phase despite provision of antiemetic prophylaxis.8

1.1.2 Pathophysiology of CINV

The pathophysiology of CINV is complex and not entirely understood. It is likely a result of the interplay of a complex network of neuroanatomical and peripheral centres, neurotransmitters, and receptors.10 The emetic reflex is proposed to involve three key components: the vomiting center (loosely organized neuronal areas within the medulla in the brain responsible for coordinating nausea and vomiting), the area postrema (i.e. chemoreceptor trigger zone; located in the medulla in the floor of the fourth ventricle) and the visceral afferents from the gastrointestinal (GI) tract.11

The most generally accepted mechanism for acute CINV hypothesizes that chemotherapy inflicts injury to the GI tract (Figure 1.1).12 This damage causes the enterochromaffin cells, located in the lining of the GI tract, to release neurotransmitters (e.g. 5-hydroxytryptamine 3 (5-HT3), substance P). These neurotransmitters bind to their ligand-specific receptors (e.g. 5-HT3 12 receptors, neurokinin-1 (NK1) receptors) located on the terminal ends of vagal afferents. Receptors for these neurotransmitters are also found in the area postrema and nucleus tractus solitarius. Binding of neurotransmitters to the vagal afferents results in an afferent stimulus that terminates in the dorsal brain stem, primarily in the nucleus tractus solitarius. Hence, drugs that block these receptors are key to the prevention of CINV. Efferent fibers project from the dorsal vagal complex (composed of the area postrema and the nucleus tractus solitarius) to the central pattern generator located more ventrally in the brainstem (Figure 1.1). The central pattern generator is the final effecter of the emetic reflex.12 Other postulated mechanisms for CINV include the direct interaction of chemotherapy with the area postrema and interactions with structures in the temporal lobe (e.g. amygdala).12

Figure 1.1 Pathways by which chemotherapeutic agents may produce an emetic response (Reproduced with permission from Hesketh PJ. Chemotherapy-induced nausea and vomiting. N Engl J Med. 2008;358(23):2482-94, Copyright Massachusetts Medical Society.)

AP, area postrema; NTS, nucleus tractus solitarius

Different mechanisms for delayed and anticipatory nausea and vomiting are hypothesized. Substance P is thought to play a primary role in mediating the vomiting response in the delayed phase. It binds to NK1 receptors in the area postrema and nucleus tractus solitarius which triggers the vomiting reflex.9 In contrast, anticipatory CINV is thought to involve a neuropsychiatric pathway with Pavlovian classical conditioning postulated to be the primary mechanism. That is, with repeated chemotherapy administration (unconditioned stimulus) and nausea/vomiting (unconditioned response), an aspect of chemotherapy administration (e.g. clinic scents, nurses,

treatment room, etc.) becomes a conditioned stimulus for nausea/vomiting (conditioned response).13

My thesis will primarily focus on the acute phase of CINV since this is when aprepitant, the subject matter of my thesis, is currently recommended for use in children.14-16

1.1.3 Emetogenicity Classification

Emetogenicity is the propensity of a drug to cause vomiting or retching. It is the only known risk factor for CINV in children.17 Chemotherapeutic agents can be classified as being either highly, moderately, low or minimally emetogenic based on the reported incidence of vomiting when the agent is given in the absence of prophylaxis (Table 1.1).8 This classification system is widely accepted by the oncology community (Pediatric Oncology Group of Ontario (POGO), American Society of Clinical Oncology (ASCO), European Society for Medical Oncology (ESMO), Multinational Association of Supportive Care in Cancer (MASCC)).15, 17, 18

Table 1.1 Chemotherapy emetogenicity classification8 Chemotherapy Emetogenicity Definition High >90% frequency of emesis in the absence of effective prophylaxis Moderate 30-90% frequency of emesis in the absence of effective prophylaxis Low 10-30% frequency of emesis in the absence of effective prophylaxis Minimal <10% frequency of emesis in the absence of effective prophylaxis

The emetogenicity of a chemotherapy agent may be dose-related. For example, depending on the dose of methotrexate that is administered, the drug may be classified as highly emetogenic chemotherapy (HEC), moderately emetogenic chemotherapy (MEC) or low emetogenic chemotherapy (LEC).17

1.2 Prevention of Acute Chemotherapy-Induced Nausea and Vomiting in Children

The discussion of the prevention of CINV will focus on the acute phase, since as mentioned previously, this is where aprepitant, the subject matter of my thesis, is currently recommended for use in children by evidence-based clinical practice guidelines.14-16

Updates of three prominent clinical practice guidelines for the prevention of acute CINV in children were published in 2017. The recommendations made by each of these guidelines are summarized in Table 1.2.14-16 The full version of the focused update of POGO’s guideline for the prevention of acute CINV is presented in Chapter 2.16

Recommendations are made based on the emetogenic risk of a patient’s chemotherapy regimen. All three guidelines generally make similar recommendations, although the strengths or levels of confidence in these recommendations differ slightly between them. This is likely a result of the different methodological approaches to article selection and guideline recommendation development taken by each guideline panel. Both the MASCC/ESMO and the ASCO guidelines made their recommendations based on pediatric randomized controlled trial (RCT) evidence only, whereas the POGO guideline recommendations are based on RCTs, prospective observational studies, retrospective observational studies and case reports. In addition, while POGO followed the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to formulating its recommendations,16 ASCO followed Guidelines Into Decision Support methodology,15 and MASCC/ESMO followed MASCC and ESMO specific criteria that have previously been established.14 Furthermore, the POGO guideline is the only one that makes recommendations specific to children <6 months where there is no evidence to support the use of aprepitant.

Overall, complete acute chemotherapy-induced vomiting (CIV) control rates in RCTs for children receiving HEC have ranged from 48%19 to 65%20 with the administration of aprepitant 21 plus a 5-HT3 receptor antagonist with or without dexamethasone. While this is not ideal and better therapies are needed, aprepitant in combination with a 5-HT3 receptor antagonist and dexamethasone is currently the most effective antiemetic regimen available for children receiving HEC.

Table 1.2 Summary of recommendations made by three clinical practice guidelines for the prevention of acute CINV in children Guideline Recommendation (Strength of recommendation/Level of Confidence) MASCC/ESMO ASCO 201715 POGO 201716 201714 1 month to 1 month to Age Group Pediatric patients ≥6 months <18 years <6 months High Emetogenic Risk Chemotherapy 5-HT receptor 5-HT receptor 5-HT receptor 3 3 5-HT receptor 3 antagonist + antagonist + 3 antagonist + No contraindications antagonist + dexamethasone + dexamethasone + dexamethasone + to antiemetics dexamethasone aprepitant aprepitant aprepitant (Strong) (Strong) (High) (Strong) 5-HT receptor 5-HT receptor 5 HT receptor Contraindication to 3 3 3 antagonist + antagonist + antagonist + aprepitant (e.g. drug not applicable dexamethasone dexamethasone dexamethasone interaction) (Strong) (Moderate) (Strong) Contraindication to 5-HT receptor dexamethasone (e.g. palonosetron + 3 palonosetron + antagonist + palonosetron acute lymphoblastic aprepitant aprepitant aprepitant (Weak) leukemia, brain (Strong) (Strong) (Moderate) tumor) Contraindication to no no palonosetron aprepitant + not applicable recommendation recommendation (Weak) dexamethasone Moderate Emetogenic Risk Chemotherapy 5-HT receptor 5-HT receptor 3 3 5-HT receptor antagonist + No contraindications antagonist + antagonist + 3 dexamethasone to antiemetics dexamethasone dexamethasone (Strong) (Strong) (Moderate) 5-HT3 receptor 5-HT3 receptor 5-HT3 receptor Contraindication to antagonist + antagonist + palonosetron antagonist + dexamethasone aprepitant aprepitant (Weak) aprepitant (Weak) (Moderate) (Weak) Contraindication to no no palonosetron aprepitant + not applicable recommendation recommendation (Weak) dexamethasone Low Emetogenic Risk Chemotherapy ondansetron or 5-HT receptor No contraindications 3 ondansetron or granisetron granisetron antagonist to antiemetics (Strong) (Strong) (Moderate) Minimal Emetogenic Risk Chemotherapy no routine no routine No contraindications no routine prophylaxis prophylaxis prophylaxis to antiemetics (Strong) (Strong) (Moderate)

1.3 Aprepitant

Currently, aprepitant is the only NK1 receptor antagonist recommended by pediatric clinical 14-16 practice guidelines for the prevention of acute CINV, and the only NK1 receptor antagonist available as a single agent product on the Canadian market. Aprepitant is also only approved for use in adults in Canada.22 However, there is clinical trial evidence that will be discussed in section 1.3.5 to support its use in children 6 months and older. The recommended adult dose of aprepitant for the prevention of CINV is 125 mg on Day 1 of chemotherapy followed by 80 mg on Days 2 and 3.22 The guideline-recommended dose of aprepitant for children 6 months and older is 3 mg/kg (maximum: 125 mg) on Day 1, followed by 2 mg/kg (maximum: 80 mg) on Days 2 and 3.16 The pediatric dosing recommendation is based on one large RCT conducted in children aged 6 months to 17 years.20

1.3.1 Mechanism of Action

23 Aprepitant is a NK1 receptor antagonist. By competitively binding to NK1 receptors, substance P (a regulatory peptide that is released from enterochromaffin cells following chemotherapy administration) is unable to bind to NK1 receptors found in the vagal afferents in the GI tract and the dorsal vagal complex. Activation of the vomiting reflex is therefore prevented.24

1.3.2 Pharmacokinetics

Pharmacokinetic data available from clinical studies for both adults and children is summarized in Table 1.3. The available pediatric data is scant and consists of: 1) a published study in 17 children aged 11 to 17 years;25 2) a description of pharmacokinetic study findings from ClinicalTrials.gov26 and 3) data submitted to the United States Food and Drug Administration (FDA)27 and the European Medicines Agency (EMA).28

Absorption: Aprepitant is slowly absorbed primarily in the small intestine. The absorption is saturable.29, 30 Aprepitant is marketed as a nanoparticle formulation to help improve its bioavailability.29 A phase IIb study demonstrated a 3.5-fold increase in aprepitant exposure when a 100 mg aprepitant dose was administered to adults as the nanoparticle formulation versus a micronized particle tablet formulation.30, 31 The mean oral bioavailability of the aprepitant 125 mg and 80 mg nanoparticle capsules in adults in a fasting state is 59% (95% confidence interval (CI): 53% to 65%) and 67% (95% CI: 62% to 73%), respectively, relative to an intravenous 2 mg 7

stable isotope-labelled aprepitant dose.32 The administration of a high fat meal has been shown to increase the area under the plasma concentration versus time curve (AUC) of the 80 mg and

125 mg capsule by 9% and 20% and the maximum concentration (Cmax) by 14% and 25%, respectively.32 The study authors did not consider this difference to be clinically important and aprepitant is recommended to be given with or without food.32

The bioavailability of aprepitant in children has not been studied.27 In the FDA and EMA’s clinical pharmacology review of the aprepitant oral suspension, a pediatric population pharmacokinetic model developed by Merck & Co. is described.27, 28 This model demonstrated that the mean aprepitant exposure (AUC) was somewhat lower in children than adults with the pediatric dosing regimen of 3 mg/kg on Day 1, and 2 mg/kg on Days 2 and 3. These slight differences in exposure are more likely a result of differences in aprepitant metabolism (see below) than absorption processes, since passive and active transport for drug absorption in infants are believed to reach adult levels by 4 months of age.33 Nevertheless, these differences in aprepitant exposure were not deemed to be clinically important as observed aprepitant trough concentrations remained within the plateau phase of the previously established concentration- response curve for adults (refer to 1.3.3) and antiemetic efficacy was observed with this pediatric dosing regimen.27

Distribution: Aprepitant is widely distributed, highly protein bound (>95%) and able to cross the blood brain barrier.29, 34 Based on the previously mentioned population pharmacokinetic model, body weight and age have shown to be significant covariates for aprepitant’s apparent volume of distribution in children.27 However, the impact of this on aprepitant’s efficacy in a child is adjusted for in the recommended pediatric dosing regimen.27 In addition, the drug’s ability to cross the blood brain barrier in children 6 months and older is not expected to differ from adults since the blood brain barrier of a child is similar to an adult’s by 4 months of age.35

Metabolism: Aprepitant is extensively metabolized by the liver through N- and O-dealkylation, primarily via cytochrome P450 (CYP) 3A4 and to a lesser extent via CYP1A2 and CYP2C19.36 There is no active metabolite. In addition to being a CYP3A4 substrate, aprepitant is also a moderate inhibitor of CYP3A4.36

The impact of CYP3A4 ontogeny on aprepitant metabolism in children has not been directly evaluated. Generally, an infant’s CYP3A4 activity reaches adult levels by the first year of life.37

After this time, a child’s CYP3A4 activity exceeds adult levels by 20% until adulthood.37 Given that aprepitant is primarily metabolized by CYP3A4, CYP3A4 ontogeny is expected to have a significant impact on a child’s exposure to aprepitant. This may explain the slightly lower aprepitant AUC that was observed in children compared to adults based on the previously mentioned population pharmacokinetic model.28 However, the pediatric aprepitant dose is also higher on a mg/kg basis compared to the recommended adult dose (i.e. 3 mg/kg vs. 125 mg in a 70 kg adult: 1.8 mg/kg). Hence, the impact of CYP3A4 ontogeny is likely accommodated by the recommended pediatric dose.27

Elimination: Aprepitant is primarily eliminated by biliary and urinary excretion of its metabolites.29 There is no evidence to suggest that this differs between adults and children 6 months and older.27, 28, 34, 38

Aprepitant pharmacokinetic variability: The interpatient variability of aprepitant in adults is considered to be low by the EMA relative to its large safety margin: coefficient of variation 29 (CV%) for AUC is about 30% and for Cmax about 23%. Larger variability has been observed in pediatric patients,27 likely a result of differing age groups and small sample sizes. The CV% for

AUC and Cmax in children range from 29-65% and 51-89%, respectively, depending on the age group (Table 1.3).27 The greatest variability is seen in patients 6 to 12 years old with CV% for 27 AUC and Cmax of 65% and 89%, respectively.

Table 1.3 Summary of aprepitant pharmacokinetic data in children and adults Age group PK Parameter 0.5 to 2 to 6 to 11 to 17 >18 years26,32,34 <2 years26, 27 <6 years26, 27 <12 years26, 27 years25 Number or 6 6 7 17 12 patients Oral Oral Oral Formulation Oral capsule Oral capsule suspension suspension suspension Dose 3 mg/kg 3 mg/kg 3 mg/kg 125 mg 125 mg 460b 554b Mean C ± SD 24 538 ± 490a 279 ± 152a 711 ± 636a (95% CI: 345 to (95% CI: 420 to (ng/mL) 612) 730) 1208b 1539b Mean C ± SD max 1810 ± 925 1840 ± 933 1800 ± 1610 (95% CI: 999.6 (95% CI: 1339 (ng/mL) to 1459) to 1769) 4 Mean T ± SD max 7.3 ± 8.28 4.9 ± 2.20 6.4 ± 7.84 4c (95% CI: 4.0 to (hours) 5.0)c 15,840 19,455b Mean AUC ± 21,100 24,400 ± (95% CI: 0-24h 17,300 ± 5060 (95% CI: 17,975 SD (ng∙hr/mL) ± 11,800 15,800g 12,910 to to 21,057) 19,430)b Mean Elimination 6.2 ± 4.12e 9.2 ± 5.57f 10.8 ± 4.27f --- 9 to 13d Half-life ± SD (hours) SD, standard deviation; CI, confidence interval; Tmax, time to maximum concentration; C24, concentration 24 hours post- aprepitant dose; Cmax, maximum concentration; AUC0-24h, area under the concentration versus time curve from 0 to 24 hours aconcentration is reported as 24 hours post chemotherapy dose (i.e. 25 hours post-aprepitant dose) bGeometric mean c Tmax is reported as median; distribution-free confidence interval based on Wilcoxon sign-rank test drange of mean half-lives (number of patients unknown) ebased on data from 3 patients fbased on data from 5 patients gbased on data from 6 patients

1.3.3 Pharmacokinetic-Pharmacodynamic Relationship

A phase II aprepitant dose ranging study evaluated the following three dosing regimens for the prevention of CINV in adult cancer patients: 40 mg on Day 1 and 25 mg on Days 2-5 (40 mg/25 mg), 125 mg on Day 1 and 80 mg on Days 2-5 (125 mg/80 mg) and 375 mg on Day 1 and 250 mg on Days 2-5 (375 mg/250 mg).39 The results of this study demonstrated that there was no apparent benefit of the higher 375 mg/250 mg dosing regimen versus the 125 mg/80 mg dosing regimen and that the 125 mg/80 mg dosing regimen had superior efficacy compared to the 40 mg/25 mg regimen.

Positron emission tomography (PET) studies in healthy adult males were conducted to establish a correlation between aprepitant plasma concentrations and the binding of aprepitant to NK1 receptors in the brain.40 The results of these studies demonstrated that aprepitant plasma

40 concentrations of ≥100 ng/mL result in NK1 receptor blockade of ≥90% (Figure 1.2). Based on the aprepitant concentrations observed with each of the three aforementioned dosing regimens and the efficacy seen in clinical studies, study investigators concluded that NK1 receptor blockade of >95% is needed for maximum antiemetic efficacy of aprepitant.40 90% receptor blockade of NK1 receptors, seen with aprepitant concentrations of 100 ng/mL, provides significant but less than maximum efficacy for the prevention of CIV.40

In children, the trough concentrations that were observed at 24 hours post-dose with the 3 mg/kg dosing (Table 1.3) were observed to be within the plateau phase of this previously established concentration-response curve for adults (i.e. >100 ng/mL; Figure 1.2).27, 28 In their submission to the FDA and EMA, Merck & Co. used this as justification, along with the clinical trial data, to support the aprepitant pediatric dosing regimen.27, 28

Figure 1.2 NK1 receptor occupancy with various aprepitant dosing regimens (obtained from EMA assessment report, October 22 2015)28

1.3.4 Adult Experience

A meta-analysis evaluating the efficacy of NK1 receptor antagonists for CINV prevention, examined 9 studies (N=4240 patients) involving aprepitant.21 The rate of CIV (vomiting, retching and use of rescue antiemetic agents) in the overall phase (acute plus delayed phases) was lower among patients given aprepitant in combination with a 5-HT3 receptor antagonist and dexamethasone compared to the rate of CIV in patients receiving a 5-HT3 receptor antagonist plus dexamethasone (35.7 versus 50.5%; odds ratio 0.53 (95% CI 0.45 to 0.61)).21 Based on MASCC guideline development principles where a 10% or greater improvement in CIV control warrants a change in guideline recommendations, the findings of the meta-analysis demonstrate a clinically significant improvement in CIV control with aprepitant.41 In fact, it is the standard of care for adult cancer patients receiving HEC to receive aprepitant as recommended by the current MASCC/ESMO and ASCO guidelines for CINV prevention in adults.15, 42

1.3.5 Pediatric Experience

Over the past few years the pediatric evidence to support the use of aprepitant for the prevention of CINV has increased. Several clinical studies,19, 20, 25, 43-48 including four RCTs,19, 20, 25, 49 have evaluated the contribution of aprepitant to CIV control in children with cancer. All published evidence has demonstrated the effectiveness of aprepitant in preventing CIV in children receiving HEC and, in some cases, MEC.19, 20, 25, 43-48 A summary of evidence can be found in Appendix A (Supplementary Tables A2-A5).

A 2017 meta-analysis of three published pediatric RCTs that included 451 patients aged 0.5 to 19 years demonstrated a 52% relative risk (RR) reduction (RR 0.48, 95% CI: 0.34-0.67) of overall

CIV when aprepitant was given in combination with a 5-HT3 receptor antagonist ± 50 dexamethasone versus a 5-HT3 receptor antagonist ± dexamethasone. This is a pronounced improvement in CIV control. The results of this meta-analysis were driven by a pivotal, large placebo-controlled RCT conducted by Kang et al. This trial was conducted in 307 children aged 6 months to 17 years receiving MEC or HEC and demonstrated that when aprepitant was administered with a 5-HT3 receptor antagonist with or without a corticosteroid, more children experienced complete acute CIV control (no vomiting, no retching, and no use of rescue medication) during the first 24 hours after aprepitant administration compared to placebo plus a 20 5-HT3 receptor antagonist with or without a corticosteroid (66% versus 52%; p=0.0135). The

other two RCTs by Gore at al25 and Bakhshi et al19 were smaller, enrolling 46 and 93 pediatric patients, respectively. Both studies also demonstrated a greater proportion of patients experiencing complete control of acute CIV with aprepitant versus without aprepitant (Gore et al: 61% vs 39%, p-value not provided; Bakhshi et al: 48% vs 12%, p<0.001).

In light of the recent pediatric evidence to support the use of aprepitant, principally the trial by Kang et al,20 it is now approved in the United States and Europe for use in children aged 6 months and older for the prevention of CINV.34, 51 The aprepitant 25 mg/mL oral suspension that was used in the Kang et al study is marketed in these jurisdictions.34, 51

As mentioned in Section 1.2, the POGO evidence-based clinical practice guidelines were updated in 2017 and recommend the use of aprepitant in children as young as 6 months in light of the growing body of evidence (Chapter 2).16

1.3.6 Aprepitant Safety

Adults: The most common adverse effects associated with the use of aprepitant in adults include: diarrhea, stomach pain, upset stomach, dizziness, hiccups, fatigue, constipation, headache, and loss of appetite.34 Rare adverse effects reported include: anxiety, fever with increased risk of infection, dry mouth, conjunctivitis (eye discharge and itching), excessive sweating, flushing, painful burning urination, itching, muscle cramp or pain, and taste disturbance. Many of the adverse effects listed may be attributable to the chemotherapy and other drugs being administered concurrently rather than to aprepitant.

Dos Santos et al evaluated the safety of aprepitant given in combination with standard therapy

(5-HT3 receptor antagonist plus dexamethasone) versus standard therapy alone in a meta-analysis of 17 trials involving 8740 patients.21 Evaluation was limited to the adverse events reported after the first chemotherapy study block in each study. Hiccups (p=0.03) and fatigue/asthenia (p=0.01) were found to be more common with aprepitant.

Substance P is a known modulator of the immune system and regulates its action via the NK1 receptor; however, it is not known whether NK1 blockade (e.g. by aprepitant) is actually beneficial or harmful in infection.29 The risk of severe infection associated with aprepitant was assessed in three trials involving 1480 patients in the aforementioned meta-analysis. An early dose-finding study of aprepitant conducted in adult cancer patients had found a higher incidence

of infection-related serious adverse events with aprepitant in combination with a 5-HT3 receptor antagonist and dexamethasone versus without aprepitant (13% vs 4.2%). However, investigators suggested that the increased risk of infection was likely due to increased exposure to corticosteroids because the same infection risk was not seen when dexamethasone doses were reduced and given in combination with aprepitant.39 Dos Santos et al found that there was no increased risk of fever and neutropenia associated with aprepitant use, but the risk of severe infection (Common Terminology Criteria for Adverse Events (CTCAE) grade 3 and 4) was significantly higher in patients receiving aprepitant in meta-analysis (odds ratio 3.10; 95% CI: 1.69 to 5.67).21 Aprepitant’s influence on the immune system is an area that requires further investigation and is outside the scope of this thesis.

Children: Though sample sizes in pediatric studies are small, aprepitant has been shown to be relatively safe and well-tolerated in children.19, 20, 25, 43, 45, 47 Adverse effects that have been noted include nausea, vomiting, hiccups, neutropenia, leukopenia, hypokalemia,20, 25 anemia, thrombocytopenia20, and headache.19 Although Gore et al reported higher rates of febrile neutropenia with aprepitant versus placebo,25 rates of febrile neutropenia were not found to increase with aprepitant use in a 2017 meta-analysis of three pediatric RCTs (RR 1.02, 95% CI: 0.66-1.58).50 Similar to adults, it is unclear what role aprepitant plays on the immune system in children. It should be noted that no pediatric study has evaluated the safety of aprepitant administration in the long-term or its impact on the duration of neutropenia. In all of the RCTs included in the meta-analysis, patients were either followed up until their next chemotherapy cycle19, 20 or 29 days post-aprepitant dose.20, 25 Overall, the adverse effects reported were often very similar to those experienced in the placebo arm of the study and may be a result of the administration of concurrent medications such as other antiemetic agents or chemotherapy.19, 20, 25

1.3.7 Aprepitant-Drug Interactions

Current pediatric guidelines for the prevention of acute CINV recommend against the use of aprepitant in the presence of a known or suspected interaction with the patient’s chemotherapy.16 When aprepitant is administered as 125 mg on Day 1 followed by 80 mg on Days 2 and 3 it initially acts as a moderate CYP3A4 inhibitor; one week later, it causes a weak CYP3A4 inducing effect.34, 52-54 It is also a weak CYP2C9 inducer.34, 52 Hence, when used for the prevention of acute CINV, aprepitant has the potential to interact with many other drugs that are metabolized via CYP3A4 and CYP2C9. A moderate CYP3A4 inhibitor is defined as a drug that 14

increases the AUC of a sensitive index drug (e.g. midazolam) by 200% to 500%.55 A weak CYP3A4 or 2C9 inducer decreases the AUC of a sensitive index drug (e.g. midazolam and tolbutamide, respectively) by 20% to less than 50%.55 A systematic review of aprepitant-drug interactions is presented in Chapter 3 of this thesis. Note that in this review, drugs evaluated for an interaction with aprepitant are termed victim drugs. A brief synopsis of aprepitant-drug interactions follows, including results from an update of the literature search completed for the 2017 systematic review.

CYP3A4 inhibition: As a moderate CYP3A4 inhibitor, aprepitant increases or is anticipated to increase the plasma concentrations of drugs which are metabolized via CYP3A4, such as dexamethasone.56, 57 Since CYP3A4 is the most common liver enzyme involved in drug metabolism, the potential for drug interactions is high.58 However, the potential for an interaction via CYP3A4 inhibition may not predict the clinical significance of co-administration of all drugs in question. For example, although docetaxel is extensively metabolized via CYP3A4, co- administration of aprepitant does not lead to clinically or statistically significant changes in the pharmacokinetics or to the toxicity of docetaxel.59 Aprepitant’s effects on CYP3A4 are likely mitigated by docetaxel’s alternate routes of elimination.52 The long term consequences of increased chemotherapy dose intensity due to concurrent administration of aprepitant have not been assessed, but may include toxicities associated with cumulative chemotherapy doses such as cardiomyopathy, renal or urinary tract toxicities, and pulmonary fibrosis.60

In contrast, aprepitant clearance is decreased and plasma concentrations are increased when it is administered together with CYP3A4 inhibitors (e.g. ketoconazole, itraconazole, clarithromycin and diltiazem) and are reduced when administered together with CYP3A4 inducers (e.g. rifampin, carbamazepine and phenytoin).34 Aprepitant is relatively well-tolerated and has a wide therapeutic index. Though increased aprepitant dose intensity may potentially lead to higher rates of dose-related adverse effects, these are likely not to be of any clinical significance. However, lower aprepitant dose intensity may result in lack of antiemetic efficacy and breakthrough CINV.

CYP2C9 induction: Aprepitant also has the potential to reduce plasma concentrations and the AUC of drugs that are metabolized by CYP2C9, such as warfarin and phenytoin.34

Other: Although the exact mechanism is not clearly elucidated, aprepitant may decrease the effectiveness of hormonal contraception,34 likely as a result of CYP enzyme induction resulting in lower ethinyl estradiol and progesterone levels.61

Systematic Review Update: An update of the systematic review literature search was conducted on February 7th, 2018. No new drug-drug interactions with aprepitant or its intravenous prodrug form, fosaprepitant, were identified. However, there were four new studies found that would have met the inclusion criteria of the 2017 systematic review; one of which investigated an interaction that was not included in the initial review. This was a retrospective study describing the lack of a pharmacokinetic interaction between aprepitant and methotrexate.48 The other three articles described interactions that were previously identified in the initial systematic review: a retrospective study describing the infusion site-reaction when fosaprepitant and anthracycline- based chemotherapy are administered peripherally,62 a case report of ifosfamide-induced encephalopathy in the presence of aprepitant,63 and changes in the international normalized ratio with the concomitant administration of warfarin and aprepitant.64 The fully published version of an abstract that was originally included in the systematic review was also identified.65

1.4 Project Rationale and Purpose of Studies

CINV is a significant problem in children, affecting both the quality of life of the child and their parents.1 Aprepitant is an agent that has been demonstrated to significantly improve CINV 19, 20, 25 control rates in children. As a result, aprepitant plus a 5-HT3 receptor antagonist plus dexamethasone or, when corticosteroids are contraindicated, aprepitant plus a 5-HT3 receptor antagonist are recommended for the prevention of acute CINV in the current guidelines.14-16 The focused update of the POGO guideline is presented in Chapter 2.16 The Children’s Oncology Group, the largest pediatric oncology research collaborative in the world, has endorsed this guideline and it is the standard of care for the prevention of CINV in children.

However, there are barriers to the provision of aprepitant-containing CINV prophylaxis to children with cancer. First, aprepitant, as discussed in section 1.3.7, is a moderate CYP3A4 inhibitor. As such, there is the potential for numerous aprepitant-drug interactions. Current clinical practice guidelines for the prevention of acute CINV in children advise that aprepitant not be given routinely when children are to receive chemotherapy that is known or suspected to interact with aprepitant.16 Hence, it becomes important to ascertain which potential interactions

are clinically significant and which are not. Thus, a systematic review of drug interactions with aprepitant was undertaken to ascertain clinically significant interactions with aprepitant (Chapter 3). The results of this systematic review will help guide clinicians to be aware of drugs, particularly antineoplastic agents that result in a clinically significant interaction and those that do not. Hence, children who can benefit from aprepitant can receive it and those who may be at increased risk of harm can avoid it.

The second, and arguably, the largest barrier to the use of aprepitant is the lack of a commercially available oral liquid formulation in Canada. Aprepitant is commercially available in Canada as 125 mg and 80 mg regular-release nanoparticle capsules.22 Many children, and even some adults, are unable to swallow capsules and therefore are unable to be administered this effective medication. The availability of an oral liquid formulation with known stability and bioavailability relative to the capsule would surmount this barrier. An oral aprepitant 20 mg/mL suspension formulation has been developed that is prepared using the contents of the 125 mg commercially available capsule.66 This oral suspension maintains 90% of its labeled potency for at least 90 days in the refrigerator. The instructions for preparing this oral suspension have been previously published,66 and it is currently being used by institutions such as The Hospital for Sick Children. However, the bioavailability of this oral suspension relative to that of the capsule is unknown. Aprepitant is manufactured as a nanoparticle formulation to help improve its bioavailability.29 It is unclear if the aprepitant nanoparticles are compromised when the beads of the aprepitant capsule are crushed and triturated in the preparation of the oral suspension such that absorption of the drug is reduced. Thus, the focus of Chapter 4 of this thesis is a prospective, randomized, 2-period, crossover study that was undertaken in healthy adult volunteers to determine the bioavailability of the aprepitant oral suspension relative to the capsule. This information will give healthcare professionals confidence in prescribing this extemporaneous oral suspension and, ultimately, help improve CINV control for their patients unable to swallow capsules.

Given that aprepitant is the only NK1 receptor antagonist recommended by clinical practice guidelines for the prevention of acute CINV in children and has the potential to significantly improve CINV control in children, it is imperative that we overcome the barriers of drug-drug interactions and formulation so that children may benefit from this effective medication.

1.5 References

1. Dupuis LL, Milne-Wren C, Cassidy M, Barrera M, Portwine C, Johnston DL, et al. Symptom assessment in children receiving cancer therapy: the parents' perspective. Support Care Cancer. 2010;18(3):281-99.

2. Hinds PS, Gattuso JS, Billups CA, West NK, Wu J, Rivera C, et al. Aggressive treatment of non-metastatic osteosarcoma improves health-related quality of life in children and adolescents. Eur J Cancer. 2009;45(11):2007-14.

3. Roscoe JA, Morrow GR, Hickok JT, Stern RM. Nausea and vomiting remain a significant clinical problem: trends over time in controlling chemotherapy-induced nausea and vomiting in 1413 patients treated in community clinical practices. J Pain Symptom Manage. 2000;20(2):113-21.

4. Lorusso D, Bria E, Costantini A, Di Maio M, Rosti G, Mancuso A. Patients' perception of chemotherapy side effects: Expectations, doctor-patient communication and impact on quality of life - An Italian survey. Eur J Cancer Care (Engl). 2017;26(2).

5. Schnell FM. Chemotherapy-induced nausea and vomiting: the importance of acute antiemetic control. Oncologist. 2003;8(2):187-98.

6. Mustian KM, Darling TV, Janelsins MC, Jean-Pierre P, Roscoe JA, Morrow GR. Chemotherapy-Induced Nausea and Vomiting. US Oncol. 2008;4(1):19-23.

7. Stewart DJ. Cancer therapy, vomiting, and antiemetics. Can J Physiol Pharmacol. 1990;68(2):304-13.

8. Dupuis LL, Boodhan S, Holdsworth M, Robinson PD, Hain R, Portwine C, et al. Guideline for the prevention of acute nausea and vomiting due to antineoplastic medication in pediatric cancer patients. Pediatr Blood Cancer. 2013;60(7):1073-82.

9. Rapoport BL. Delayed Chemotherapy-Induced Nausea and Vomiting: Pathogenesis, Incidence, and Current Management. Front Pharmacol. 2017;8:19.

10. Janelsins MC, Tejani MA, Kamen C, Peoples AR, Mustian KM, Morrow GR. Current pharmacotherapy for chemotherapy-induced nausea and vomiting in cancer patients. Expert Opin Pharmacother. 2013;14(6):757-66.

11. Hesketh PJ. Understanding the pathobiology of chemotherapy-induced nausea and vomiting. Providing a basis for therapeutic progress. Oncology (Williston Park). 2004;18(10 Suppl 6):9-14.

12. Hesketh PJ. Chemotherapy-induced nausea and vomiting. N Engl J Med. 2008;358(23):2482-94.

13. Kamen C, Tejani MA, Chandwani K, Janelsins M, Peoples AR, Roscoe JA, et al. Anticipatory nausea and vomiting due to chemotherapy. Eur J Pharmacol. 2014;722:172-9.

14. Dupuis LL, Sung L, Molassiotis A, Orsey AD, Tissing W, van de Wetering M. 2016 updated MASCC/ESMO consensus recommendations: Prevention of acute chemotherapy- induced nausea and vomiting in children. Support Care Cancer. 2017;25(1):323-31.

15. Hesketh PJ, Kris MG, Basch E, Bohlke K, Barbour SY, Clark-Snow RA, et al. Antiemetics: American Society of Clinical Oncology Clinical Practice Guideline Update. J Clin Oncol. 2017;35(28):3240-61.

16. Patel P, Robinson PD, Thackray J, Flank J, Holdsworth MT, Gibson P, et al. Guideline for the prevention of acute chemotherapy-induced nausea and vomiting in pediatric cancer patients: A focused update. Pediatr Blood Cancer. 2017;64(10).

17. Dupuis LL, Boodhan S, Sung L, Portwine C, Hain R, McCarthy P, et al. Guideline for the classification of the acute emetogenic potential of antineoplastic medication in pediatric cancer patients. Pediatr Blood Cancer. 2011;57(2):191-8.

18. Jordan K, Chan A, Gralla RJ, Jahn F, Rapoport B, Warr D, et al. 2016 Updated MASCC/ESMO consensus recommendations: Emetic risk classification and evaluation of the emetogenicity of antineoplastic agents. Support Care Cancer. 2017;25(1):271-5.

19. Bakhshi S, Batra A, Biswas B, Dhawan D, Paul R, Sreenivas V. Aprepitant as an add-on therapy in children receiving highly emetogenic chemotherapy: a randomized, double-blind, placebo-controlled trial. Support Care Cancer. 2015;23(11):3229-37.

20. Kang HJ, Loftus S, Taylor A, DiCristina C, Green S, Zwaan CM. Aprepitant for the prevention of chemotherapy-induced nausea and vomiting in children: a randomised, double- blind, phase 3 trial. Lancet Oncol. 2015;16(4):385-94.

21. dos Santos LV, Souza FH, Brunetto AT, Sasse AD, da Silveira Nogueira Lima JP. Neurokinin-1 receptor antagonists for chemotherapy-induced nausea and vomiting: a systematic review. J Natl Cancer Inst. 2012;104(17):1280-92.

22. Health Canada Drug Product Database. Emend (aprepitant) Product Monograph [Internet]. Kirkland (QC): Merck Canada Inc.; 2014 January 22 [cited 2018 January 8]. Available from: https://pdf.hres.ca/dpd_pm/00023565.PDF.

23. Dando TM, Perry CM. Aprepitant: a review of its use in the prevention of chemotherapy- induced nausea and vomiting. Drugs. 2004;64(7):777-94.

24. Apfel CC, Malhotra A, Leslie JB. The role of neurokinin-1 receptor antagonists for the management of postoperative nausea and vomiting. Curr Opin Anaesthesiol. 2008;21(4):427-32.

25. Gore L, Chawla S, Petrilli A, Hemenway M, Schissel D, Chua V, et al. Aprepitant in adolescent patients for prevention of chemotherapy-induced nausea and vomiting: a randomized, double-blind, placebo-controlled study of efficacy and tolerability. Pediatr Blood Cancer. 2009;52(2):242-7.

26. ClinicalTrials.gov. A Study of MK-0869 (Aprepitant) and MK-0517 (Fosaprepitant) in Pediatric Participants Receiving Chemotherapy (MK-0869-134) [Internet]. Bethesda (MD): National Library of Medicine; 2000 January 7 [updated 2017 June 2; cited 2018 March 12].

Available from: https://clinicaltrials.gov/ct2/show/study/NCT00818259?term=aprepitant§=X9870156&view =results

27. U.S. Food and Drug Administration. Clinical Pharmacology Review [Internet]. Silver Spring (MD): U.S. Food and Drug Administration; 2016 January [cited 1 March 2018]. Available from: https://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/DevelopmentResources/U CM467340.pdf

28. European Medicines Agency. Emend (aprepitant) assessment report [Internet]. London: European Medicines Agency; 2015 October 22 [cited 2018 January 8]. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Assessment_Report_- _Variation/human/000527/WC500200826.pdf.

29. European Medicines Agency. Emend (aprepitant) scientific discussion [Internet]. London: European Medicines Agency; 2006 September 5 [cited 2018 January 8]. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_- _Scientific_Discussion/human/000527/WC500026534.pdf.

30. Wu Y, Loper A, Landis E, Hettrick L, Novak L, Lynn K, et al. The role of biopharmaceutics in the development of a clinical nanoparticle formulation of MK-0869: a Beagle dog model predicts improved bioavailability and diminished food effect on absorption in human. Int J Pharm. 2004;285(1-2):135-46.

31. Olver I, Shelukar S, Thompson KC. Nanomedicines in the treatment of emesis during chemotherapy: focus on aprepitant. Int J Nanomedicine. 2007;2(1):13-8.

32. Majumdar AK, Howard L, Goldberg MR, Hickey L, Constanzer M, Rothenberg PL, et al. Pharmacokinetics of aprepitant after single and multiple oral doses in healthy volunteers. J Clin Pharmacol. 2006;46(3):291-300.

33. Kearns GL, Abdel-Rahman SM, Alander SW, Blowey DL, Leeder JS, Kauffman RE. Developmental pharmacology--drug disposition, action, and therapy in infants and children. N Engl J Med. 2003;349(12):1157-67.

34. Merck & Co., Inc. Emend (aprepitant) Product Monograph [Internet]. Merck Sharp & Dohme Corp.; 2017 May [cited 2018 January 8]. Available from: http://www.merck.com/product/usa/pi_circulars/e/emend/emend_pi.pdf.

35. Webster, R. Blood brain barrier maturation: implications for drug development [Internet]. London: European Medicines Agency; 2009 [cited 2018 April 6]. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Presentation/2009/11/WC500009793. pdf.

36. Sanchez RI, Wang RW, Newton DJ, Bakhtiar R, Lu P, Chiu SH, et al. Cytochrome P450 3A4 is the major enzyme involved in the metabolism of the substance P receptor antagonist aprepitant. Drug Metab Dispos. 2004;32(11):1287-92.

37. de Wildt SN, Kearns GL, Leeder JS, van den Anker JN. Cytochrome P450 3A: ontogeny and drug disposition. Clin Pharmacokinet. 1999;37(6):485-505.

38. European Medicines Agency. Aloxi: EPAR - Product Information [Internet]. London: European Medicines Agency; 2015 April [cited 2016 August 2]. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_- _Product_Information/human/000563/WC500024259.pdf.

39. Chawla SP, Grunberg SM, Gralla RJ, Hesketh PJ, Rittenberg C, Elmer ME, et al. Establishing the dose of the oral NK1 antagonist aprepitant for the prevention of chemotherapy- induced nausea and vomiting. Cancer. 2003;97(9):2290-300.

40. U.S. Food and Drug Administration. Drug Approval Package Emend (Aprepitant) [Internet]. Silver Spring (MD): U.S. Food and Drug Administration; 2003 March [cited 2018 March 1]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2003/21- 549_Emend.cfm.

41. Roila F, Herrstedt J, Aapro M, Gralla RJ, Einhorn LH, Ballatori E, et al. Guideline update for MASCC and ESMO in the prevention of chemotherapy- and radiotherapy-induced nausea and vomiting: results of the Perugia consensus conference. Ann Oncol. 2010;21:v232-v43.

42. Herrstedt J, Roila F, Warr D, Celio L, Navari RM, Hesketh PJ, et al. 2016 Updated MASCC/ESMO Consensus Recommendations: Prevention of Nausea and Vomiting Following High Emetic Risk Chemotherapy. Support Care Cancer. 2017;25(1):277-88.

43. Choi MR, Jiles C, Seibel NL. Aprepitant use in children, adolescents, and young adults for the control of chemotherapy-induced nausea and vomiting (CINV). J Pediatr Hematol Oncol. 2010;32(7):e268-71.

44. Bauters TG, Verlooy J, Robays H, Benoit Y, Laureys G. Emesis control by aprepitant in children and adolescents with chemotherapy. Int J Clin Pharm. 2013;35(6):1021-4.

45. Bodge M, Shillingburg A, Paul S, Biondo L. Safety and efficacy of aprepitant for chemotherapy-induced nausea and vomiting in pediatric patients: a prospective, observational study. Pediatr Blood Cancer. 2014;61(6):1111-3.

46. Duggin K, Tickle K, Norman G, Yang J, Wang C, Cross SJ, et al. Aprepitant reduces chemotherapy-induced vomiting in children and young adults with brain tumors. J Pediatr Oncol Nurs. 2014;31(5):277-83.

47. Shillingburg A, Biondo L. Aprepitant and fosaprepitant use in children and adolescents at an academic medical center. J Pediatr Pharmacol Ther. 2014;19(2):127-31.

48. Felix-Ukwu F, Reichert K, Bernhardt MB, Schafer ES, Berger A. Evaluation of aprepitant for acute chemotherapy-induced nausea and vomiting in children and adolescents with acute lymphoblastic leukemia receiving high-dose methotrexate. Pediatr Blood Cancer. 2018;65(2).

49. Long CK, H.; Mueller, E. . A pilot study comparing the addition of olanzapine or aprepitant in an antiemetic regimen for highly emetogenic chemotherapy. Pediatr Blood Cancer. 2015;60:174.

50. Okumura LM, D'Athayde Rodrigues F, Ferreira MAP, Moreira LB. Aprepitant in pediatric patients using moderate and highly emetogenic protocols: a systematic review and meta-analyses of randomized controlled trials. Br J Clin Pharmacol. 2017;83(5):1108-17.

51. European Medicines Agency. Emend (aprepitant) product information (Internet). London: European Medicines Agency; 2017 November 10 [cited 2018 January 8]. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_- _Product_Information/human/000527/WC500026537.pdf.

52. Patel P, Leeder JS, Piquette-Miller M, Dupuis LL. Aprepitant and fosaprepitant drug interactions: a systematic review. Br J Clin Pharmacol. 2017;83(10):2148-62.

53. Shadle CR, Lee Y, Majumdar AK, Petty KJ, Gargano C, Bradstreet TE, et al. Evaluation of potential inductive effects of aprepitant on cytochrome P450 3A4 and 2C9 activity. J Clin Pharmacol. 2004;44(3):215-23.

54. Stoch SA, Gargano C, Valentine J, Braun MP, Murphy MG, Fedgchin M, et al. Double- blind crossover study to assess potential differences in cytochrome P450 3A4 activity in healthy subjects receiving ondansetron plus dexamethasone, with and without aprepitant. Cancer Chemother Pharmacol. 2011;67(6):1313-21.

55. U.S. Food and Drug Administration. Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers [Internet]. Silver Spring (MD): U.S. Food and Drug Administration; 2017 November 14 [cited 2016 October 11]. Available from: http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractio nsLabeling/ucm093664.htm

56. McCrea JB, Majumdar AK, Goldberg MR, Iwamoto M, Gargano C, Panebianco DL, et al. Effects of the neurokinin1 receptor antagonist aprepitant on the pharmacokinetics of dexamethasone and methylprednisolone. Clin Pharmacol Ther. 2003;74(1):17-24.

57. Nakade S, Ohno T, Kitagawa J, Hashimoto Y, Katayama M, Awata H, et al. Population pharmacokinetics of aprepitant and dexamethasone in the prevention of chemotherapy-induced nausea and vomiting. Cancer Chemother Pharmacol. 2008;63(1):75-83.

58. Ohno Y, Hisaka A, Suzuki H. General framework for the quantitative prediction of CYP3A4-mediated oral drug interactions based on the AUC increase by coadministration of standard drugs. Clin Pharmacokinet. 2007;46(8):681-96.

59. Nygren P, Hande K, Petty KJ, Fedgchin M, van Dyck K, Majumdar A, et al. Lack of effect of aprepitant on the pharmacokinetics of docetaxel in cancer patients. Cancer Chemother Pharmacol. 2005;55(6):609-16.

60. Children's Oncology Group [Internet]. Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent and Young Adult Cancer. 2013 October [cited 2018 March 12]. Available from: http://www.survivorshipguidelines.org/pdf/LTFUGuidelines_40.pdf. 22

61. Lee CR. Drug interactions and hormonal contraception. Trends in Urology, Gynaecology & Sexual Health. 2009;14(3):23-6.

62. Boccia R, Geller R, Clendeninn N, Ottoboni T. A retrospective chart review of hypersensitivity and infusion-site adverse events (isaes) associated with fosaprepitant iv in patients receiving anthracycline and cyclophosphamide (ac)-based chemotherapy. Support Care Cancer. 2017;25 (2 Supplement 1):S64.

63. Kataria P, Kendre P, Patel A. Ifosfamide-induced encephalopathy precipitated by aprepitant: A rarely manifested side effect of drug interaction. Journal of Pharmacology and Pharmacotherapeutics. 2017;8(1):38-40.

64. Takaki J, Ohno Y, Yamada M, Yamaguchi R, Hisaka A, Suzuki H. Assessment of Drug- Drug Interaction between Warfarin and Aprepitant and Its Effects on PT-INR of Patients Receiving Anticancer Chemotherapy. Biol Pharm Bull. 2016;39(5):863-8.

65. Hsyu PH, Pignataro DS, Matschke K. Effect of aprepitant, a moderate CYP3A4 inhibitor, on bosutinib exposure in healthy subjects. European Journal of Clinical Pharmacology. 2017;73(1):49-56.

66. Dupuis LL, Lingertat-Walsh K, Walker SE. Stability of an extemporaneous oral liquid aprepitant formulation. Support Care Cancer. 2009;17(6):701-6.

Chapter 2 Guideline for the Prevention of Acute Chemotherapy-Induced Nausea and Vomiting in Pediatric Cancer Patients: A Focused Update

« Heading styles 1-9 for thesis body: Heading 1 »

The contents of this chapter have been published in Pediatric Blood & Cancer and are included in this thesis with permission of John Wiley & Sons, Inc.: Patel P, Robinson PD, Thackray J, Flank J, Holdsworth MT, Gibson P, Orsey A, Portwine C, Freedman J, Madden JR, Phillips R, Sung L, Dupuis LL. Guideline for the prevention of acute chemotherapy‐induced nausea and vomiting in pediatric cancer patients: A focused update. Pediatric Blood & Cancer. 2017 October; 64(10). E-pub April 2017. Copyright 2017 Wiley Periodicals, Inc.

All authors were involved in the conception and planning of the work that led to development of this clinical practice guideline. All authors also provided their input to the various drafts of the guideline and their approval of the final draft submitted for publication.

This guideline is founded on three systematic reviews. I was involved with the literature review (with assistance from a library scientist) and title and abstract screening for 2 of the 3 reviews. I completed full-text screening and data extraction for all 3 of the systematic reviews. I drafted the updated recommendations based on the review of the evidence with guidance from Dr. Lee Dupuis (my supervisor). These draft recommendations were reviewed and discussed by the guideline panel until consensus was reached. Risk of bias was assessed by Dr. Lee Dupuis and Dr. Paula Robinson (guideline methodologist). I prepared the initial draft manuscript and made changes based on the guideline panel’s feedback.

2.1 Abstract

This update of the 2013 clinical practice guideline provides clinicians with guidance regarding the use of aprepitant and palonosetron for the prevention of acute chemotherapy-induced nausea and vomiting (CINV) in children. The recommendations were based on three systematic reviews. Substantive changes were made to the guideline recommendations including: the inclusion of palonosetron to the 5-HT3 antagonists recommended for children receiving highly emetogenic chemotherapy (HEC) and the recommendation of aprepitant for children ≥6 months of age receiving HEC. To optimize CINV control in children, future work must focus on closing critical research gaps.

2.2 Introduction

This focused update of the 2013 Guideline for the Prevention of Acute Nausea and Vomiting due to Antineoplastic Medication in Pediatric Cancer Patients1 was prompted by the recent publication of several pediatric randomized controlled trials evaluating aprepitant and palonosetron for the prevention of acute chemotherapy-induced nausea and vomiting (CINV). The overall aim of the guideline update is to optimize acute CINV control in children by providing guidance on the use of aprepitant and palonosetron to health care professionals who care for children with cancer or for those receiving chemotherapy for hematopoietic stem cell transplant conditioning. This guideline update may be of most interest to physicians, pharmacists, nurse practitioners, physician assistants and nurses. Optimal acute CINV control is defined as no vomiting, no retching, no nausea, no use of antiemetic agents other than those given for CINV prevention and no nausea-related change in the child’s usual appetite and diet on each day that chemotherapy is administered and for 24 hours after administration of the last chemotherapy agent of the chemotherapy block. Nausea is defined as the subjective sensation that one might vomit. The recommendations of this guideline update, like those of the previous guideline, are most applicable to chemotherapy-naïve cancer patients 1 month to 18 years of age. This update is focused on aprepitant and palonosetron and is provided pending a full guideline update.

2.3 Methods

2.3.1 Guideline panel and health questions addressed

The membership of the interprofessional CINV Guideline Panel and conflict of interest declarations are provided in Appendix A (Section A). No panel member had a conflict of interest that precluded participation. Health questions addressed in the 2013 guideline were reviewed and those that were relevant to this update were brought forward (Table 2.1).

2.3.2 Evidence identification and review

Three systematic reviews were conducted in consultation with a library scientist. The database search strategies, eligibility criteria and PRISMA flowcharts for each systematic review are provided in Appendix A (Sections B-D). Two reviewers independently screened the titles and abstracts; evaluated the full-text of potentially relevant citations for eligibility and assessed risk of bias of included randomized trials using the Cochrane Collaboration tool.2 Disagreements were resolved by a third reviewer. The three systematic reviews were: (a) Primary studies of aprepitant or palonosetron describing the rate of CINV control in children; (b) Meta-analyses evaluating palonosetron compared to other 5-hydroxytryptamine type 3 (5-

HT3) antagonists for acute CINV prophylaxis in adults or children. (c) Primary studies describing palonosetron pharmacokinetic disposition.

Evidence tables were compiled to summarize the findings of all included studies and were organized by chemotherapy emetogenicity (minimal, low, moderate and high) based on the pediatric emetogenicity classification guideline3 or, when this was not possible, by the chemotherapy emetogenicity classification used by the authors of included studies. For studies where subjects received chemotherapy of different levels of emetogenicity (e.g. highly emetogenic chemotherapy (HEC) or moderately emetogenic chemotherapy (MEC)) and where study investigators did not report CINV control rates for these two groups separately, the extracted data were categorized under the lower emetogenicity level.

Evidence summaries of adverse events were restricted to those reported in included randomized trials since adverse event reporting in these studies was more likely to be completed in a systematic fashion.

Recommendations were developed based on the evidence identified from the systematic reviews and refined through panel discussions. The associated potential health benefits versus risks were considered for each recommendation. Strong recommendations (i.e. most individuals should receive the recommended intervention)4 were made when the panel was certain that the potential benefits of the recommended intervention outweighed the risk of harm. Differences in opinion were resolved by consensus. The quality of evidence and strength of recommendations were assessed using the Grades of Recommendation Assessment, Development and Evaluation system5, 6 by one author and confirmed through discussion by the remaining panel members. If consensus was unable to be reached, a decision was made by the majority of panel members by a vote.

2.3.3 External review

A draft version of the guideline was reviewed by international experts in pediatric CINV. The committee considered the responses received before finalizing the recommendations (Appendix A: Supplementary Tables A15-A16).

2.3.4 Guideline updates

A comprehensive update to the 2013 Guideline for the Prevention of Acute Nausea and Vomiting due to Antineoplastic Medication in Pediatric Cancer Patients1 is planned for 2018.

2.4 Results

Results of the searches for the three systematic reviews and their respective evidence tables are presented in Appendix A (Supplementary Figure A1, Supplementary Tables A2-A8; Supplementary Figure A2, Supplementary Table A10; Supplementary Figure A3, and Supplementary Table A12).

CINV control: The systematic review of primary papers describing the chemotherapy-induced vomiting (CIV) control rate in children receiving aprepitant or palonosetron identified 2,374 references. Of these, 70 were reviewed in full-text and 12 met the criteria for inclusion (aprepitant: 57-11; palonosetron: 712-18) (Appendix A: Supplementary Figure A1). No evidence

regarding the use of aprepitant or palonosetron in children receiving chemotherapy of low or minimal emetogenicity was identified.

Between-screener agreement regarding inclusion of full-text articles was almost perfect (kappa = 90.6, 95% CI 77.7 to 100%).19 Tables 2.2 and 2.3 summarize the characteristics of included studies. An assessment of the risk of bias in randomized studies is provided in Appendix A: Supplementary Table A8. Data extracted with respect to CINV control and adverse events are presented in Appendix A: Supplementary Tables A2-A7.

Adverse events: Two and four fully published, randomized controlled pediatric trials evaluating aprepitant7, 10 (202 children) and palonosetron 12, 14, 16, 17 (421 children), respectively, were included in the adverse event summary. The incidence of drug-related adverse events reported in these trials was less than 5%; serious drug-related adverse events were reported even less frequently (Appendix A: Supplementary Tables A6-A7). No adverse events attributed to aprepitant or palonosetron prompted drug discontinuation. Furthermore, adverse events associated with the use of either agent resolved quickly and none were fatal. The panel therefore considered both aprepitant and palonosetron to be associated with a low risk of acute harm when used appropriately.

CINV control with palonosetron versus other 5-HT3 antagonists: A single meta-analysis of randomized trials conducted predominantly in adults met criteria for inclusion in the systematic review evaluating the efficacy of palonosetron versus other 5-HT3 antagonists for the prevention of acute CINV20 (Appendix A: Supplementary Table A10).

Pharmacokinetic disposition of palonosetron: Twenty articles evaluating palonosetron pharmacokinetics were included in this systematic review.21-40 (Appendix A: Supplementary Table A12).

The recommendations for the prevention of acute CINV in children receiving HEC or MEC are summarized in Table 2.1 and Figure 2.1. The rationale for each revised recommendation is provided as follows.

2.4.1 Health Question #1: What pharmacological interventions provide optimal control of acute CINV in children receiving highly emetogenic chemotherapy (HEC)?

Recommendation 1.1 We recommend that children at least 6 months old receiving HEC which is not known or suspected to interact with aprepitant, receive granisetron or ondansetron or palonosetron plus dexamethasone* plus aprepitant. Strong recommendation; moderate quality evidence. Changes from 2013: Aprepitant recommended for children ≥6 months and inclusion of palonosetron as an alternate 5-HT3 antagonist. *see Recommendations 1.4, 1.5 and 1.6 for information regarding children who cannot receive dexamethasone.

Recommendation 1.2 We recommend that children <6 months old receiving HEC receive granisetron or ondansetron or palonosetron plus dexamethasone. Strong recommendation; moderate quality evidence.

Change from 2013: Inclusion of palonosetron as an alternate 5-HT3 antagonist.

Recommendation 1.3 We recommend that children 6 months or older receiving HEC, which is known or suspected to interact with aprepitant, receive granisetron or ondansetron or palonosetron plus dexamethasone. Strong recommendation; moderate quality evidence.

Change from 2013: Inclusion of palonosetron as an alternate 5-HT3 antagonist.

Aprepitant: Three pediatric randomized trials 7, 10, 11 evaluating the use of aprepitant met criteria for inclusion in the evidence used to develop Recommendation 1.1. The first compared acute CIV control rates provided by ondansetron plus dexamethasone plus either aprepitant or placebo (48% vs 12%; p<0.001).10 The second described complete CIV control rates in a subset of 200 children receiving HEC and ondansetron with/without dexamethasone plus either aprepitant or placebo for CINV prophylaxis (65% versus 51%; panel calculated p = 0.047; panel calculated 95% confidence interval (CI) of the difference between groups: 0.2% to 28%).7 The dexamethasone dose administered in this trial was not standardized and the proportion of children in this subset who received it is unknown. The third was a small crossover study that found no difference in CIV control rates in children receiving ondansetron plus dexamethasone plus either olanzapine or aprepitant (77% vs. 79%; panel calculated p=1).11 29

Palonosetron: A meta-analysis20 and three pediatric randomized trials 12, 16, 17informed these recommendations. The meta-analysis20 synthesized the findings of 16 randomized controlled trials involving 6,083 adults and children who received HEC or MEC. Complete acute CIV control rates observed in patients receiving dexamethasone plus palonosetron or another 5-HT3 antagonist were comparable (odds ratio: 1.14; 95% CI: 0.88-1.49).

Two of the pediatric trials evaluated palonosetron monotherapy versus ondansetron monotherapy.16, 17 One observed similar rates of complete acute CIV control between study arms (70% vs. 65%; p=0.633)17 whereas the second observed improved CIV control in the palonosetron study arm (92% vs. 72%; panel calculated p = 0.017; panel calculated 95% CI of the difference between groups: 4 % to 36%).16 The third pediatric trial used a non-inferiority design. The use of dexamethasone in this trial was discretionary and, if given, the dose was not standardized. High-dose palonosetron was found to be non-inferior to ondansetron with respect to complete acute response rates in children receiving HEC or MEC.12 Although not a study aim, the rates of complete acute response in children receiving HEC were: high-dose palonosetron: 51%; low-dose palonosetron: 43% and ondansetron: 41%.

Summary: In developing these recommendations, the trial demonstrating increased complete

CIV control rates in children given aprepitant in combination with a 5-HT3 antagonist and dexamethasone was valued highly by the panel.10 Aprepitant is not recommended for use in children less than 6 months of age because it has not been studied in this age group for the purpose of CINV prophylaxis. Aprepitant, a moderate CYP3A4 inhibitor, continues to be recommended for use in conjunction with chemotherapy which is not known or suspected to interact. A list of antineoplastic agents which are CYP3A4 substrates is included as a supplementary table in the 2013 clinical practice guideline.1 In recommending palonosetron as a possible 5-HT3 antagonist, high value was placed on the meta-analysis which indicated that complete CIV control rates were comparable in adult and pediatric patients receiving different 5- 20 HT3 antagonists in combination with dexamethasone. The findings of non-inferiority between high-dose palonosetron and ondansetron with/without dexamethasone were also considered.12

Recommendation 1.4 We recommend that children at least 6 months old receiving HEC, which is not known or suspected to interact with aprepitant, and who cannot receive dexamethasone for CINV prophylaxis receive palonosetron plus aprepitant. Strong recommendation; moderate

quality evidence. Changes from 2013: Addition of aprepitant and recommendation of palonosetron as the preferred 5-HT3 antagonist. Deletion of chlorpromazine and nabilone.

Recommendation 1.5 We suggest that children less than 6 months old receiving HEC and who cannot receive dexamethasone for CINV prophylaxis receive palonosetron. Weak recommendation; moderate quality evidence.

Changes from 2013: Recommendation of palonosetron as the preferred 5-HT3 antagonist. Deletion of chlorpromazine and nabilone.

Recommendation 1.6 We suggest that children receiving HEC, which is known or suspected to interact with aprepitant, and who cannot receive dexamethasone receive palonosetron. Weak recommendation; moderate quality evidence.

Changes from 2013: Recommendation of palonosetron as the preferred 5-HT3 antagonist. Deletion of chlorpromazine and nabilone.

Pediatric oncology patients may be unable to receive dexamethasone for CINV prophylaxis due to protocol restrictions or toxicity.1

Aprepitant: While no study that met criteria for inclusion in this systematic review specifically evaluated CINV control following prophylaxis with a 5-HT3 antagonist plus aprepitant without dexamethasone in children receiving HEC, one trial, mentioned previously, included an unknown number of children who received this regimen.7 The higher complete CIV control rates in children receiving ondansetron with/without dexamethasone plus either aprepitant or placebo observed in this trial (65% versus 51%; panel calculated p = 0.047; panel calculated 95% CI of the difference between groups: 0.2% to 28%) indirectly supports the use of a 5-HT3 antagonist plus aprepitant.

Palonosetron: These recommendations were informed by the previously described adult-focused meta-analysis20 and three pediatric randomized trials12, 16, 17. The meta-analysis20 observed a greater likelihood of preventing acute CIV in patients receiving palonosetron alone compared to monotherapy with other 5-HT3 antagonists (odds ratio: 1.52; 95% CI: 1.15-2.02). Two of the pediatric randomized trials,16, 17 one of which was included in the meta-analysis,16 compared palonosetron monotherapy versus ondansetron monotherapy. These trials differed substantially 31

in their definitions of the acute phase. The trial which likely enrolled children receiving multiple day therapy17 reported complete CIV control rates achieved during the entire acute phase (i.e. greater than 24 hours in duration). No difference was observed between study arms (palonosetron vs ondansetron: 70% vs 65%; p=0.633). In contrast, the second trial16 compared CIV control rates in the first 24 hours of chemotherapy. Higher complete CIV control rates were observed in children who received palonosetron (92 vs 72%; panel calculated p = 0.017; panel calculated 95% CI of the difference between groups: 4 % to 36%). Indirect support of the recommendation of palonosetron as the preferred 5-HT3 antagonist when dexamethasone cannot be given is also provided in the non-inferiority trial mentioned previously.12 Although not a primary study aim, rates of complete acute control for the subset of children who received 1-day HEC and who did not receive dexamethasone were: low-dose palonosetron: 61%; high-dose palonosetron: 60%; and ondansetron: 42%.

Summary: In developing Recommendation 1.4, value was placed on improved CIV control reported in a subset of patients within a larger randomized controlled trial who received ondansetron plus aprepitant.7 As explained earlier, aprepitant is not recommended for children

<6 months old. In recommending palonosetron as the preferred 5-HT3 antagonist in recommendations 1.4, 1.5 and 1.6, high value was placed on the meta-analysis20 demonstrating increased acute CIV control with palonosetron versus other 5-HT3 antagonists in the absence of dexamethasone.

The guideline panel discussed the inclusion of adjunctive antiemetic agents such as those recommended in the 2013 guideline 1 (i.e. chlorpromazine or nabilone) for children less than 6 months old, as well as for children of all ages unable to receive both aprepitant and corticosteroids. However, the absence of direct evidence to support the efficacy or safety of these agents in the younger age group or to support their efficacy in combination with a 5-HT3 antagonist in any age group dissuaded the guideline panel from making such a recommendation.

Since direct evidence to support the preferred use of palonosetron monotherapy for children <6 months old receiving HEC is not available, Recommendation 1.5 is a weak recommendation. That is, although the majority of individuals would want the suggested intervention, many would not and the decision to implement the recommendation should be based on patient, clinician and institutional values and preferences.4 Recommendation 1.6 is also a weak recommendation since

it is supported primarily by evidence in adult patients and because findings of pediatric trials are inconsistent.

2.4.2 Health Question #2: What pharmacological interventions provide optimal control of acute CINV in children receiving moderately emetogenic chemotherapy (MEC)?

Recommendation 2.1 We recommend that children receiving MEC receive granisetron or ondansetron or palonosetron plus dexamethasone*. Strong recommendation; moderate quality evidence.

Change from 2013: Inclusion of palonosetron as an alternate 5-HT3 antagonist. * see recommendations 2.2, 2.3 and 2.4 for information regarding children who cannot receive dexamethasone.

Palonosetron: The previously described meta-analysis,20 and five pediatric studies (two randomized controlled trials,12, 14 two prospective observational studies13, 18 and one retrospective observational study15) informed this recommendation. The meta-analysis reported comparable complete acute CIV control rates with palonosetron plus dexamethasone versus other 5-HT3 antagonists in combination with dexamethasone (odds ratio: 1.14; 95% CI: 0.88-1.49) in adults and children receiving MEC or HEC.20 This analysis was not presented separately for patients receiving MEC.

The previously described non-inferiority trial provided complete CIV control rates in the subset of 339 patients receiving MEC.12 Complete acute CIV control rates of 63%, 60% and 67% were observed in these children receiving high-dose palonosetron, low-dose palonosetron or ondansetron, respectively. An unknown number of children in each study arm also received a non-standardized dose of dexamethasone. In addition, ondansetron versus palonosetron was evaluated in a randomized controlled trial in children receiving HEC (122 cycles) or MEC (38 cycles). However, results were not reported separately for these groups.14 Children receiving HEC also received dexamethasone in this trial. Complete acute CIV control rates were comparable between the two study arms (70% versus 75%; p-value=0.479).

Furthermore, results from the three single-arm observational studies also described good CIV control rates with palonosetron. The two prospective studies13, 18 reported complete acute CIV

control rates in children receiving MEC and palonosetron of 84% and 98%. The retrospective review of 47 chemotherapy blocks in 43 patients receiving HEC or MEC as conditioning for hematopoietic stem cell transplant reported a complete acute CINV control rate of 68%.15

Summary: The recommendation to include palonosetron among the recommended 5-HT3 antagonists is based on the meta-analysis20 and the included prospective pediatric studies 12, 14 demonstrating similar CIV control rates following palonosetron versus other 5-HT3 antagonists combined with dexamethasone in children receiving MEC. Aprepitant is not included in this recommendation as there is no direct, high quality evidence demonstrating the superiority of aprepitant for CINV prophylaxis for children receiving MEC without a contraindication for corticosteroids. While a greater proportion of patients achieved CIV control with aprepitant versus placebo in the randomized controlled trial7 included in the evidence summary, the number of patients who received dexamethasone in this subset of patients is unclear.

Recommendation 2.2 We suggest that children 6 months or older receiving MEC who cannot receive dexamethasone for CINV prophylaxis receive granisetron or ondansetron or palonosetron plus aprepitant. Weak recommendation; moderate quality evidence.

Change from 2013: Addition of aprepitant and inclusion of palonosetron as an alternate 5-HT3 antagonist.

Recommendation 2.3 We suggest that children less than 6 months receiving MEC who cannot receive dexamethasone for CINV prophylaxis receive palonosetron. Weak recommendation; moderate quality evidence.

Change from 2013: Recommendation of palonosetron as the preferred 5-HT3 antagonist. Deletion of chlorpromazine, metoclopramide and nabilone.

Recommendation 2.4 We suggest that children receiving MEC, which is known or suspected to interact with aprepitant, and who cannot receive dexamethasone receive palonosetron. Weak recommendation; moderate quality evidence.

Change from 2013: Recommendation of palonosetron as the preferred 5-HT3 antagonist. Deletion of chlorpromazine, metoclopramide and nabilone.

Pediatric oncology patients may be unable to receive dexamethasone for CINV prophylaxis due to protocol restrictions or toxicity.1 34

Aprepitant: The randomized trial conducted by Kang et al7 was considered by the panel in making this recommendation. An unknown number of children who received aprepitant in combination with ondansetron were included in this study. The proportion of complete acute CIV control with aprepitant (plus ondansetron with/without dexamethasone) vs. placebo (plus ondansetron with/without dexamethasone) for children receiving MEC was 70% vs. 55% (panel calculated p = 0.15; panel calculated 95% CI of the difference between groups: -5% to 35%).

Palonosetron: The evidence base described for Recommendation 2.1 also informed the development of this recommendation. The meta-analysis20 supports the preference for palonosetron over other 5-HT3 antagonists in the absence of dexamethasone. In addition, a randomized crossover trial observed similar complete CIV control rates in children receiving palonosetron or ondansetron (70% vs 75%; p=0.479). It is important to note that children who participated in this trial received either HEC or MEC and an unknown proportion also received dexamethasone for CINV prophylaxis. Furthermore, the non-inferiority trial described earlier reported complete acute CIV control rates in the very small subset of children receiving one-day MEC with dexamethasone as follows: low-dose palonosetron: 57%; high-dose: palonosetron: 88%; and ondansetron: 73%.12 Complete acute CIV control rates reported in prospective observational studies for children receiving MEC with palonosetron monotherapy ranged from 68 to 91%.13, 15, 18

Summary: The panel developed Recommendations 2.2 to 2.4 with the appreciation that children who cannot receive dexamethasone are more vulnerable to breakthrough and refractory CINV. These recommendations draw on the evidence of efficacy in children receiving HEC. Value was also placed on the large pediatric randomized controlled trials describing CIV control in the subsets of children receiving MEC and ondansetron plus aprepitant7 and palonosetron monotherapy.12

Given the broad range of emetogenicity risk classified as MEC (30 to 90%),3 the panel recognizes that clinicians may wish to reserve palonosetron for children who cannot receive dexamethasone who are about to receive chemotherapy with an emetogenicity risk at the higher end of the MEC range.

The panel also considered the inclusion of antiemetic agents such as chlorpromazine, metoclopramide and nabilone for use when aprepitant is not an option. However, the lack of direct evidence to support the efficacy and safety of these agents in children less than 6 months and the absence of high quality evidence describing their efficacy in combination with a 5-HT3 antagonist dissuaded the guideline panel from recommending their use.

Recommendations 2.2, 2.3 and 2.4 are weak recommendations because uncertainty exists regarding the extent of the improvement in CIV control that can be achieved with the implementation of these recommendations due to the lack of direct supporting evidence.

2.4.3 Health Question #3: What doses of aprepitant and palonosetron are known to be effective in children receiving chemotherapy?

Recommendation 3.1 We suggest the following aprepitant dose for children 6 months and older: Day 1: 3 mg/kg (maximum: 125 mg) PO x 1; Days 2 and 3: 2 mg/kg (maximum: 80 mg) PO once daily. Weak recommendation; moderate quality evidence. Change from 2013: Inclusion of a dose for children 6 months to 12 years old. Change in dose recommended for children 12 years of age and older.

No true aprepitant dose-finding pediatric studies have been published. Information provided within a randomized controlled trial7 was primarily considered in the development of this recommendation (Appendix A: Supplementary Tables A2-A5). The aprepitant dose used in this trial was derived using data from phase I and phase III pediatric studies and was designed to achieve similar values of pharmacokinetic parameters in children as those achieved in adults after administration of recommended aprepitant doses. An aprepitant oral liquid was not administered in most other pediatric aprepitant studies; thus, doses were often assigned based on weight categories to accommodate the available capsule strengths (125mg, 80mg and 40mg). When converted to mg/kg dosing, aprepitant doses of 2 to 5.3 mg/kg/day on day 1 and 1.2 to 5.3 mg/kg/day on days 2 and 3 were given in one such trial.10

Summary: This recommendation places a high value on the dose simulation information discussed within a pediatric randomized control trial7 and on evidence that this dose improves CIV control in children during the first 24 hours after receipt of HEC or MEC. The recommended dose is in agreement with the aprepitant dose approved for pediatric use by the

United States’ Food and Drug Administration (FDA) and the European Medicines Agency (EMA).41, 42 Questions, however, remain regarding the optimal aprepitant dose in children receiving multiple day chemotherapy and whether a single aprepitant dose would be sufficient for children receiving single day chemotherapy. As a result of these uncertainties, this is a weak recommendation.

Recommendation 3.2 We suggest the following palonosetron dose for children: 1 month to <17 years: 0.02 mg/kg IV once (max 1.5 mg/dose) pre-chemotherapy; ≥17 years: 0.25 mg/dose IV or 0.5 mg/dose PO once pre-chemotherapy. Weak recommendation; moderate quality evidence. Change from 2013: Inclusion of palonosetron dosing.

No pediatric palonosetron dose-finding studies are available. The palonosetron dose recommended for children <17 years old is based on the trial that demonstrated the non- inferiority of palonosetron 0.02 mg/kg IV compared to ondansetron 0.15 mg/kg/dose IV q4h x 3 doses.12 It is recommended that adolescents 17 to 18 years of age receive the licensed adult palonosetron dose.43-45

The palonosetron dose recommended for patients 17 years of age and older is based on a dose- finding study which concluded that 0.003 mg/kg was the lowest effective dose in adults.34 It is notable that adults weighing less than 83 kg who receive the approved adult palonosetron dose (0.25 mg IV) receive more than 0.003 mg/kg.

The pediatric palonosetron dose approved by the FDA and EMA43, 45 is 6 times greater than the recommended adult dose. Since pediatric dosing is often calculated to approximate the dose intensity (e.g. area under the curve from time 0 to infinity (AUC0-inf), maximum concentration, and time above a threshold concentration) achieved in adults, a systematic review of studies which describe palonosetron pharmacokinetic disposition in adults and children was undertaken. Findings from this review confirmed that when single palonosetron doses of 0.02 mg/kg are given to children, the dose intensity achieved exceeds that achieved when palonosetron 0.003 mg/kg doses are given to adults (Appendix A: Supplementary Table A12).

No palonosetron pharmacokinetic parameter is predictive of CINV outcomes in adults.46 However, a logistical regression exposure-relationship model developed using pediatric data 37

noted increased CIV control (no emetic episode and no use of rescue medication during the first

24 hours after the start of emetogenic chemotherapy) with increasing palonosetron AUC0-inf. This effect plateaued at an AUC0-inf of approximately 100 µg∙h/L which approximates the AUC0-inf achieved after administration of 0.02 mg/kg/dose in children.47 Since the emetogenicity of the chemotherapy received by the patients included in the model was not reported, it is not possible to determine if the association between CIV control and palonosetron AUC applies to both MEC and HEC.

Flat or non-weight based palonosetron doses have been shown to be effective in children (Appendix A: Supplementary Table A14). In two pediatric randomized controlled trials that evaluated single IV palonosetron doses of 0.25 mg, it was possible to calculate the weight-based palonosetron dosing range.16, 17 One found acute CIV control to be comparable in patients receiving either palonosetron (dose range: 0.03 mg/kg to 0.09 mg/kg) or ondansetron (70% vs 65%; p=0.633).17 In the other trial, CIV control in the palonosetron arm (dose range: 0.003 to 0.019 mg/kg/dose) was superior to that of the ondansetron study arm (92% vs 72%; p=0.0092).16 Another pediatric randomized trial14 and three single arm studies13, 15, 18 evaluated a single palonosetron dose of 0.005 mg/kg. The randomized trial noted similar CIV control rates in patients receiving HEC or MEC and palonosetron or ondansetron (70% vs 75%; p=0.479).14 The three single arm studies reported CIV control rates ranging from 68% to 98%.13, 15, 18

Summary: This recommendation places value on the results of a large randomized trial demonstrating the non-inferiority of ondansetron and palonosetron 0.02 mg/kg,12 the current pediatric IV palonosetron dose licensed by the FDA and EMA and the current adult oral palonosetron dose licensed by Health Canada.43, 45 While a 0.02 mg/kg dose is safe and effective, it may be unnecessarily high. Since other pediatric studies have demonstrated significant CIV control in patients receiving palonosetron 0.005 mg/kg and 0.01 mg/kg,13-16, 18 it is unclear if palonosetron 0.02 mg/kg is required to achieve optimal acute CIV control in children or if a lower dose could achieve comparable outcomes. In addition, optimal palonosetron dosing in children receiving multiple day chemotherapy is unknown and is an important research gap.

This is a weak recommendation because the panel is not certain that a palonosetron dose of 0.02 mg/kg is warranted for MEC and HEC.

2.4.4 Implementation Considerations

While motivated by CINV control optimization and safety, the panel recognized that the cost of aprepitant and palonosetron may be a barrier to the implementation of these recommendations. In jurisdictions where cost is a barrier to using palonosetron 0.02 mg/kg/dose and compliance with the dose approved by regulatory authorities is not a concern, it may be reasonable to initiate palonosetron at the recommended dose with a patient’s first chemotherapy block and, depending on the patients’ CINV control, to administer a lower dose with a future chemotherapy block. Administration of ondansetron or granisetron may also be reasonable. Patient and institutional values, preferences and resources should be considered when implementing guideline recommendations.

2.5 Conclusions

Recommendations for the prevention of acute CINV in children have been updated. (Table 2.1 and Appendix A: Supplementary Table A17) Significant changes have been made to the recommendations in light of new evidence supporting the use of aprepitant and palonosetron in children. However, extensive evidence gaps remain. (Table 2.4) Continual appraisal of the evidence and prospective evaluation of patient outcomes that are achieved with the implementation of these recommendations are required. Furthermore, to ensure that control of acute CINV in children is optimized future work must address critical evidence gaps.

2.6 Acknowledgments

The assistance of Ms. Elizabeth Uleryk, Library Scientist with the literature search and Ms. Ivy Zou, Dr. Winnie Seto and Dr. Masanobu Takeuchi with translations of non-English papers is gratefully acknowledged. The submission of a review from the following content reviewers is acknowledged with thanks: Ms. D. Wood and Drs. S. Bakhshi, A-M. Langevin, T. MacDonald and M. van de Wetering. We are also thankful for the administrative assistance of Ms. Sandra Cabral, the Pediatric Oncology Group of Ontario.

Table 2.1 Health questions and summary of recommendations for the prevention of acute chemotherapy-induced nausea and vomiting in pediatric cancer patients Strength of Health questions and recommendations recommendation and level of evidence5, 6 Health question #1: What pharmacological interventions provide optimal control of acute CINV in children receiving HEC? Recommendation 1.1: We recommend that children ≥6 months old receiving HEC Strong recommendation which is not known or suspected to interact with aprepitant receive: granisetron Moderate quality or ondansetron or palonosetron + dexamethasone + aprepitant. evidence Changes from 2013: Aprepitant recommended for children ≥6 months and inclusion of palonosetron as an alternate 5-HT3 antagonist. Recommendation 1.2: We recommend that children <6 months old receiving HEC Strong recommendation receive: granisetron or ondansetron or palonosetron + dexamethasone. Moderate quality Change from 2013: Inclusion of palonosetron as an alternate 5-HT3 antagonist. evidence Recommendation 1.3: We recommend that children ≥6 months receiving HEC which Strong recommendation is known or suspected to interact with aprepitant receive: granisetron or Moderate quality ondansetron or palonosetron + dexamethasone. evidence Change from 2013: Inclusion of palonosetron as an alternate 5-HT3 antagonist. Recommendation 1.4: We recommend that children ≥6 months old receiving HEC Strong recommendation which is not known or suspected to interact with aprepitant and who cannot Moderate quality receive dexamethasone for CINV prophylaxis receive: palonosetron + aprepitant. evidence Changes from 2013: Addition of aprepitant and recommendation of palonosetron as the preferred 5-HT3 antagonist. Deletion of nabilone and chlorpromazine. Recommendation 1.5: We suggest that children <6 months old receiving HEC and Weak recommendation who cannot receive dexamethasone for CINV prophylaxis receive: palonosetron. Moderate quality Changes from 2013: Recommendation of palonosetron as the preferred 5-HT3 evidence antagonist. Deletion of nabilone and chlorpromazine. Recommendation 1.6: We suggest that children receiving HEC which is known or Weak recommendation suspected to interact with aprepitant and who cannot receive dexamethasone Moderate quality receive: palonosetron. evidence Changes from 2013: Recommendation of palonosetron as the preferred 5-HT3 antagonist. Deletion of nabilone and chlorpromazine. Health Question #2: What pharmacological interventions provide optimal control of acute CINV in children receiving MEC? Recommendation 2.1: We recommend that children receiving moderately Strong recommendation emetogenic chemotherapy (MEC) receive: granisetron or ondansetron or Moderate quality palonosetron + dexamethasone. evidence Change from 2013: Inclusion of palonosetron as an alternate 5-HT3 antagonist. Recommendation 2.2: We suggest that children ≥6 months receiving MEC who Weak recommendation cannot receive dexamethasone for CINV prophylaxis receive: granisetron or Moderate quality ondansetron or palonosetron + aprepitant. evidence Change from 2013: Addition of aprepitant and inclusion of palonosetron as an alternate 5-HT3 antagonist. Recommendation 2.3: We suggest that children <6 months receiving MEC who Weak recommendation cannot receive dexamethasone for CINV prophylaxis receive: palonosetron. Moderate quality Change from 2013: Recommendation of palonosetron as the preferred 5-HT3 evidence antagonist. Deletion of chlorpromazine, metoclopramide and nabilone. CINV, chemotherapy-induced nausea and vomiting; HEC, highly emetogenic chemotherapy; MEC, moderately emetogenic chemotherapy; PO, by mouth; IV, intravenous; 5-HT3, 5-hydroxytryptamine 3 A recommendation summary table that includes the remarks for each recommendation is presented in Appendix A: Supplementary Table A17.

Strength of Health questions and recommendations recommendation and level of evidence5, 6 Recommendation 2.4: We suggest that children receiving MEC which is known or Weak recommendation suspected to interact with aprepitant and who cannot receive dexamethasone Moderate quality receive: palonosetron. evidence Change from 2013: Recommendation of palonosetron as the preferred 5-HT3 antagonist. Deletion of chlorpromazine, metoclopramide and nabilone. Health Question #3: What doses of aprepitant and palonosetron are known to be effective in children receiving chemotherapy? Recommendation 3.1: We suggest the following aprepitant dose for children ≥6 Weak recommendation months: Moderate quality Day 1: 3 mg/kg (max: 125 mg) PO x 1; evidence Days 2 and 3: 2 mg/kg (max: 80mg) PO once daily. Change from 2013: Inclusion of a dose for children 6 months to 12 years old. Change in dose recommended for children 12 years of age and older. Recommendation 3.2: We suggest the following palonosetron dose for children: Weak recommendation 1 month to < 17 years: 0.02 mg/kg IV once (max 1.5 mg/dose) pre-chemotherapy Moderate quality ≥17 years: 0.25 mg/dose IV or 0.5 mg/dose PO once pre-chemotherapy evidence Change from 2013: Inclusion of palonosetron dosing. CINV, chemotherapy-induced nausea and vomiting; HEC, highly emetogenic chemotherapy; MEC, moderately emetogenic chemotherapy; PO, by mouth; IV, intravenous; 5-HT3, 5-hydroxytryptamine 3 A recommendation summary table that includes the remarks for each recommendation is presented in Appendix A: Supplementary Table A17.

naïve

NR NR

No. of

0 (0%) 0

93 (100%) 93 (41%) 123

patients(%)

chemotherapy

18) 18)

18)

17)

- -

16)

(0.5

17.8)

years

(range),

Placebo:

7.5

14 ( 14

9.6 (1 9.6

Meanage

median age; median

12.7 (6 12.7 (5 13.1

Aprepitant:

c c

therapy

NA NA

27 18 20

No. of

blocks

chemo

genic chemotherapy; No.: number; NA: NR: applicable; Not NA: chemotherapy; genic number; No.:

13 11

104

302

No. of

patients

(66%)

: 102 : (34%)

: 200 200 :

(100%) (100%)

HEC: 93 (100%)

Emetogenicity

HEC: 13 (100%) 13 HEC:

VHEC

(No. patients; of %)

HEC/MEC

HEC/MEC: 18 blocks HEC/MEC: 18 blocks

prepitant

included in evidence base for recommendation regarding MEC; for regarding recommendation evidence base in included

b b

hasone +

vs.

aprepitant

aprepitant aprepitant

olanzapine

aprepitant

dexamethasone

aprepitant

dexamethasonevs.

Antiemetics Antiemetics evaluated

Ondansetronplacebo + +/

Ondansetron +

Ondansetrondexamet +

[Ondansetronor tropisetron or

granisetron] granisetron] dexamethasone + +

Ondansetrondexamethasone + + Ondansetrondexamethasone + + Ondansetrondexamethasone + +

Ondansetrondexamethasone + placebo +

Year

2015 2013

2015 2015 2014

Summary of included evaluating studies a Summary

ve design ve

Author

included in evidence base for recommendations regarding HEC; regarding for recommendations evidence base in included

Table 2.2 Parallel group design Parallel Long Randomized trials Bakhshi Kang Crossover groupdesign Observational studies Prospecti Bodge Retrospectivedesign Bauters emeto MEC: moderately chemotherapy; emetogenic VHEC: chemotherapy; highly emetogenic very HEC:highly reported Not a a

NR NR NR NR

No. of

14 (14%) 14

105 (21%) 105 (100%) 37

chemotherapy

naïve patients naïve (%)

15)

17)

16.9) 16.9) 16.9) 10.5)

18)

27) 26)

- - - -

- -

6.6 (2 6.6

Meanage

7.6 (2.2 7.6

alonosetron

13.9 (6 13.9 8.1 (0.2 8.1 (0.2 8.4 (0.2 8.2 (5 14.3 (2.2 14.1 (1.7 7.7

(range), years

P µg/kg: 10 Palonosetron µg/kg: 20 Ondansetron: Palonosetron: Ondansetron: Palonosetron: Ondansetron:

therapy

NA NA NA

138

160

No. of

blocks

chemo

80 37

493 100

applicable; NR: Not reported Not NR: applicable;

No. of

patients

: 47 47 :

(76%) (24%)

(100%) (100%)

: 122 blocks 122 :

Crossover groupdesign

blocks(100%)

HEC/MEC

alonosetron Emetogenicity

MEC: 44 44 MEC: blocks

MEC: 38 blocks blocks 38 MEC:

HEC:(31%) 154 HEC: 80 (100%)

MEC: 339 (69%) 339 MEC:

MEC: 138 blocks 138 MEC:

HEC:(100%) 100 H

(No. patients of (%)

median age median

b b

- -

valuating

vs. vs.

vs.

tudies tudies

(10 µg/kg) (10 +/ µg/kg) (20 +/

[+ dexamethasone [+

for HEC]for

Ondansetron Ondansetron Ondansetron

Palonosetron Palonosetron Palonosetron

Palonosetron Palonosetron

corticosteroidvs. corticosteroidvs.

ncluded

Antiemetics Antiemetics evaluated

Palonosetron Palonosetron

Ondansetron [+ dexamethasone Ondansetron[+

Palonosetron

Year

2016 2013 2008 2015 2011 2013 2010

Summary of i Summary

trospectivedesign

Author

included in evidence base for recommendation regarding MEC; MEC; regarding for recommendation base evidence in included

Vildosola

Table 2.3 Randomized trials Randomized Parallel group Parallel design Kovacs Tang Sepulveda - Patil Observational studies design Prospective Nadaraja Varrasso Re Ripaldi HEC: highly emetogenic chemotherapy; MEC: moderately emetogenic chemotherapy; NA: Not Not NA: chemotherapy; emetogenic MEC: moderately chemotherapy; emetogenic HEC:highly a a

Table 2.4 Aprepitant and palonosetron for the prevention of acute chemotherapy-induced nausea and vomiting in children: examples of evidence gaps APREPITANT  Aprepitant dosing and safety in children <6 months  Aprepitant dosing in children receiving multiple day chemotherapy  Fosaprepitant dosing in children of all ages  Evaluation of the extent of aprepitant pharmacokinetic drug interactions with commonly used pediatric chemotherapy agents  Evaluation of the efficacy and safety of adjunctive antiemetics such as chlorpromazine, nabilone and metoclopramide in children  Evaluation of the efficacy of a 5-HT3 antagonist plus aprepitant in children receiving moderately emetogenic chemotherapy who cannot receive dexamethasone PALONOSETRON  Palonosetron dosing in children receiving moderately emetogenic chemotherapy or multiple day chemotherapy  Oral palonosetron dosing  Effectiveness of palonosetron IV doses lower than 0.02 mg/kg/dose in children receiving highly emetogenic chemotherapy  Efficacy of palonosetron monotherapy in children receiving moderately or highly emetogenic chemotherapy  Comparison of the efficacy of palonosetron in conjunction with aprepitant in children  Comparison of the efficacy of palonosetron versus other 5-HT3 antagonists as monotherapy and in conjunction with dexamethasone in children

Figure 2.1 Summary of recommendations regarding antiemetic agent selection for prevention of acute CINV in children

2.7 References

1. Dupuis LL, Boodhan S, Holdsworth M, Robinson PD, Hain R, Portwine C, et al. Guideline for the prevention of acute nausea and vomiting due to antineoplastic medication in pediatric cancer patients. Pediatr Blood Cancer. 2013;60(7):1073-82.

2. Higgins J, Green S. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0. London, United Kingdom.: The Cochrane Collaboration; 2011.

3. Dupuis LL, Boodhan S, Sung L, Portwine C, Hain R, McCarthy P, et al. Guideline for the classification of the acute emetogenic potential of antineoplastic medication in pediatric cancer patients. Pediatr Blood Cancer. 2011;57(2):191-8.

4. Andrews J, Schünemannb H, Oxmand A, Pottiee K, Meerpohl J, Coelloh P, et al. GRADE guidelines: 15. Going from evidence to recommendation—determinants of a recommendation's direction and strength. Journal of Clinical Epidemiology. 2013;66(7):726-35.

5. Guyatt GH, Oxman AD, Kunz R, Falck-Ytter Y, Vist GE, Liberati A, et al. Going from evidence to recommendations. BMJ. 2008;336(7652):1049-51.

6. Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck-Ytter Y, Alonso-Coello P, et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ. 2008;336(7650):924-6.

7. Kang HJ, Loftus S, Taylor A, DiCristina C, Green S, Zwaan CM. Aprepitant for the prevention of chemotherapy-induced nausea and vomiting in children: a randomised, double- blind, phase 3 trial. Lancet Oncol. 2015;16(4):385-94.

8. Bodge M, Shillingburg A, Paul S, Biondo L. Safety and efficacy of aprepitant for chemotherapy-induced nausea and vomiting in pediatric patients: a prospective, observational study. Pediatr Blood Cancer. 2014;61(6):1111-3.

9. Bauters TG, Verlooy J, Robays H, Benoit Y, Laureys G. Emesis control by aprepitant in children and adolescents with chemotherapy. Int J Clin Pharm. 2013;35(6):1021-4.

10. Bakhshi S, Batra A, Biswas B, Dhawan D, Paul R, Sreenivas V. Aprepitant as an add-on therapy in children receiving highly emetogenic chemotherapy: a randomized, double-blind, placebo-controlled trial. Support Care Cancer. 2015;23(11):3229-37.

11. Long CK, H.; Mueller, E. . A pilot study comparing the addition of olanzapine or aprepitant in an antiemetic regimen for highly emetogenic chemotherapy. Pediatr Blood Cancer. 2015;60:174.

12. Kovacs G, Wachtel AE, Basharova EV, Spinelli T, Nicolas P, Kabickova E. Palonosetron versus ondansetron for prevention of chemotherapy-induced nausea and vomiting in paediatric patients with cancer receiving moderately or highly emetogenic chemotherapy: a randomised, phase 3, double-blind, double-dummy, non-inferiority study. Lancet Oncology. 2016;17(3):332- 44.

13. Nadaraja S, Mamoudou AD, Thomassen H, Wehner PS, Rosthoej S, Schroeder H. Palonosetron for the prevention of nausea and vomiting in children with acute lymphoblastic leukemia treated with high dose methotrexate. Pediatr Blood Cancer. 2012;59(5):870-3.

14. Patil V, Prasada H, Prasad K, Shenoy UV. Comparison of antiemetic efficacy and safety of palonosetron vs ondansetron in the prevention of chemotherapy-induced nausea and vomiting in children. J. 2015;13(6):209-13.

15. Ripaldi M, Parasole R, De Simone G, D'Amico MR, Migliorati R, Zanotta G, et al. Palonosetron to prevent nausea and vomiting in children undergoing BMT: efficacy and safety. Bone Marrow Transplantation. 2010;45(11):1663-4.

16. Sepulveda-Vildosola AC, Betanzos-Cabrera Y, Lastiri GG, Rivera-Marquez H, Villasis- Keever MA, Del Angel VW, et al. Palonosetron hydrochloride is an effective and safe option to prevent chemotherapy-induced nausea and vomiting in children. Arch Med Res. 2008;39(6):601- 6.

17. Tang L, Lin F, Yao Y. Efficacy of palonosetron hydrochloride injection in preventing gastrointestinal reactions caused by high-dose chemotherapy in osteosarcoma patients. [Chinese]. Chinese Journal of Clinical Oncology. 2013;40(3):168-70+77.

18. Varrasso G, De Grazia A, Mollace MG, Megaro G, Paiano M, Suraci S. Antiemetic efficacy of palonosetron in children receiving moderately emetogenic chemotherapy: Preliminary results. Pediatric Blood and Cancer. 2013;60:174.

19. Koch G, Landis J, Freeman J, Freeman D, Jr. , Lehnen R. A general methodology for the analysis of experiments with repeated measurement of categorical data. Biometrics. 1977;33(1):133-58.

20. Popovic M, Warr DG, Deangelis C, Tsao M, Chan KK, Poon M, et al. Efficacy and safety of palonosetron for the prophylaxis of chemotherapy-induced nausea and vomiting (CINV): a systematic review and meta-analysis of randomized controlled trials. Support Care Cancer. 2014;22(6):1685-97.

21. Ikari Y, Ogata K, Nakashima Y, Sato E, Masaki M, Katsuya H, et al. Safety and pharmacokinetic evaluation of repeated intravenous administration of palonosetron 0.75 mg in patients receiving highly or moderately emetogenic chemotherapy. Support Care Cancer. 2014;22(7):1959-64.

22. Sadaba B, del Barrio A, Campanero MA, Azanza JR, Gomez-Guiu A, Lopez-Picazo JM, et al. Randomized pharmacokinetic study comparing subcutaneous and intravenous palonosetron in cancer patients treated with platinum based chemotherapy. PLoS ONE [Electronic Resource]. 2014;9(2):e89747.

23. Calcagnile S, Lanzarotti C, Rossi G, Henriksson A, Kammerer KP, Timmer W. Effect of netupitant, a highly selective NK1 receptor antagonist, on the pharmacokinetics of palonosetron and impact of the fixed dose combination of netupitant and palonosetron when coadministered with ketoconazole, rifampicin, and oral contraceptives. Support Care Cancer. 2013;21(10):2879- 87. 47

24. Li P, Ma P, Wang Y, Tong W, Wang J, Wu C, et al. Liquid chromatography-electrospray quadrupole linear ion trap mass spectrometry method for the quantitation of palonosetron in human plasma and urine: Application to a pharmacokinetic study. J Chromatogr B Analyt Technol Biomed Life Sci. 2012;895-896:10-6.

25. Yang S, Qin F, Wang D, Li N, Li F, Xiong Z. Determination of palonosetron in human plasma by ultra performance liquid chromatography-tandem mass spectrometry and its application to a pharmacokinetic study. Journal of Pharmaceutical & Biomedical Analysis. 2012;57:13-8.

26. Maemondo M, Masuda N, Sekine I, Kubota K, Segawa Y, Shibuya M, et al. A phase II study of palonosetron combined with dexamethasone to prevent nausea and vomiting induced by highly emetogenic chemotherapy. Ann Oncol. 2009;20(11):1860-6.

27. Einhorn LH, Brames MJ, Dreicer R, Nichols CR, Cullen MT, Jr., Bubalo J. Palonosetron plus dexamethasone for prevention of chemotherapy-induced nausea and vomiting in patients receiving multiple-day cisplatin chemotherapy for germ cell cancer. Support Care Cancer. 2007;15(11):1293-300.

28. Ding L, Chen Y, Yang L, Wen A. Determination of palonosetron in human plasma by liquid chromatography-electrospray ionization-mass spectrometry. Journal of Pharmaceutical & Biomedical Analysis. 2007;44(2):575-80.

29. Shah A, DeGroot T, Apseloff G. Pharmacokinetic evaluation and safety profile of a 15- minute versus 30-second infusion of palonosetron in healthy subjects. Journal of Clinical Pharmacology. 2006;46(10):1139-45.

30. Shah AK, Hunt TL, Gallagher SC, Cullen MT, Jr. Pharmacokinetics of palonosetron in combination with aprepitant in healthy volunteers. Curr Med Res Opin. 2005;21(4):595-601.

31. Hunt TL, Gallagher SC, Cullen MT, Jr., Shah AK. Evaluation of safety and pharmacokinetics of consecutive multiple-day dosing of palonosetron in healthy subjects. Journal of Clinical Pharmacology. 2005;45(5):589-96.

32. Stoltz R, Parisi S, Shah A, Macciocchi A. Pharmacokinetics, metabolism and excretion of intravenous [l4C]-palonosetron in healthy human volunteers. Biopharm Drug Dispos. 2004;25(8):329-37.

33. Stoltz R, Cyong JC, Shah A, Parisi S. Pharmacokinetic and safety evaluation of palonosetron, a 5-hydroxytryptamine-3 receptor antagonist, in U.S. and Japanese healthy subjects. Journal of Clinical Pharmacology. 2004;44(5):520-31.

34. Eisenberg P, MacKintosh FR, Ritch P, Cornett PA, Macciocchi A. Efficacy, safety and pharmacokinetics of palonosetron in patients receiving highly emetogenic cisplatin-based chemotherapy: a dose-ranging clinical study. Ann Oncol. 2004;15(2):330-7.

35. Calcagnile S, Lanzarotti C, Gutacker M, Jakob-Rodamer V, Peter Kammerer K, Timmer W. Evaluation of the effect of food and age on the pharmacokinetics of oral netupitant and

palonosetron in healthy subjects: A randomized, open-label, crossover phase 1 study. Clin Pharm Drug Dev. 2015;4(5):377-86.

36. Shi XL, Shao FX, Song M, Hang TJ, Yang L, Wen AD, et al. Pharmacokinetics and bioavailability of palonosetron hydrochloride capsules in healthy volunteers. [Chinese]. Chinese Journal of New Drugs. 2013;22(6):681-5.

37. Sun J, Li Z, Zhang Y, Yang W, Tang S, Hu J. Study on pharmacokinetics of palonosetron hydrochloride in healthy volunteers. [Chinese]. Pharmaceutical Care and Research. 2012;12(6):465-8.

38. Dai YY, Liu P, Chen Z, Tang ZQ, Feng FY. Pharmacokinetic properties of palonosetron, a 5-hydroxytryptamine-3 receptor antagonist, in Chinese healthy subjects. [Chinese]. Chinese Journal of New Drugs. 2009;18(10):910-3.

39. Zhang W, Feng F, Le W, Wang H, Zhu L. Sensitive and selective LC-MS-MS assay for the quantification of palonosetron in human plasma and its application to a pharmacokinetic study. Chromatographia. 2008;68(3-4):193-9.

40. Spinelli T, Moresino C, Baumann S, Timmer W, Schultz A. Effects of combined netupitant and palonosetron (NEPA), a cancer supportive care antiemetic, on the ECG of healthy subjects: an ICH E14 thorough QT trial. Springerplus. 2014;3:389.

41. European Medicines Agency. Emend: EPAR - Product Information [Internet]. London: European Medicines Agency; 2016 April [cited 2016 August 2]. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_- _Product_Information/human/000527/WC500026537.pdf.

42. Merck & Co., Inc. . Emend (aprepitant) Product Monograph [Internet]. Merck Sharp & Dohme Corp.; 2015 August [cited 2015 September 15]. Available from: http://www.merck.com/product/usa/pi_circulars/e/emend/emend_pi.pdf.

43. Helsinn Healthcare SA. Aloxi: Prescribing Information [Internet]. Switzerland; Eisai Inc.; 2015 December [cited 2016 August 2]. Available from: http://www.aloxi.com/docs/pdf/PI.pdf.

44. Eisai Ltd. Aloxi Product Monograph [Internet]. Mississauga (ON): Eisai Limited; 2013 November [cited 2016 September 7]. Available from: http://ca.eisai.com/pdf/new/Aloxi%20palonosetron%20hydrochloride%20Product%20Monograp h%20March%2012%20-%202012.pdf.

45. European Medicines Agency. Aloxi: EPAR - Product Information [Internet]. London: European Medicines Agency; 2015 April [cited 2016 August 2]. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_- _Product_Information/human/000563/WC500024259.pdf.

46. European Medicines Agency. Assessment report: Aloxi [Internet]. London: European Medicines Agency; 2015 January [cited 2016 August 2]. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Assessment_Report_- _Variation/human/000563/WC500185343.pdf. 49

47. Wang J, Mehrotra N, Kim I, Lee SC, Sohrabi F, He R, et al. Exposure-Response of Palonosetron for Prevention of Chemotherapy-induced Nausea and Vomiting in Pediatric Patients. J Pediatr Gastroenterol Nutr. 2016.

Chapter 3 Drug Interactions with Aprepitant and Fosaprepitant: A Systematic Review

The contents of this chapter have been published in British Journal of Clinical Pharmacology and are included in this thesis with permission of John Wiley & Sons, Inc.: Patel P, Leeder JS, Piquette‐Miller M, Dupuis LL. Aprepitant and fosaprepitant drug interactions: a systematic review. British Journal of Clinical Pharmacology. 2017 October; 83(10): 2148-2162.E-pub June 2017. Copyright 2017 The British Pharmacological Society.

All authors were involved in the conception and planning of the work that led to development of this systematic review. All authors also provided input to all drafts and approval of the final draft submitted for publication.

I was involved at every stage of this systematic review: literature review (with assistance from a library scientist), title and abstract screening, full text screening, data extraction, data analysis, risk of bias assessment and manuscript preparation.

« Heading styles 1-9 for thesis body: Heading 1 »

3.1 Abstract

Aims: Aprepitant and fosaprepitant, commonly used for the prevention of chemotherapy-induced nausea and vomiting, alter cytochrome P450 activity. This systematic review evaluates clinically significant pharmacokinetic drug interactions with aprepitant and fosaprepitant and describes adverse events ascribed to drug interactions with aprepitant or fosaprepitant.

Methods: We systematically reviewed the literature to September 11, 2016 to identify articles evaluating drug interactions involving aprepitant/fosaprepitant. The clinical significance of each reported pharmacokinetic drug interaction was evaluated based on the United States Food and Drug Administration guidance document on conducting drug interaction studies. The probability of an adverse event reported in case reports being due to a drug interaction with aprepitant/fosaprepitant was determined using the Drug Interaction Probability Scale.

Results: 4377 publications were identified. Of these, 64 met inclusion eligibility criteria: 34 described pharmacokinetic drug interactions and 30 described adverse events ascribed to a drug interaction. Clinically significant pharmacokinetic interactions between aprepitant/fosaprepitant and bosutinib PO, cabazitaxel IV, cyclophosphamide IV, dexamethasone PO, methylprednisolone IV, midazolam PO/IV, oxycodone PO and tolbutamide PO were identified as were adverse events resulting from an interaction between aprepitant/fosaprepitant and alcohol, anthracyclines, ifosfamide, oxycodone, quetiapine, selective serotonin reuptake inhibitors/serotonin-norepinephrine reuptake inhibitors and warfarin.

Conclusions: The potential for a drug interaction with aprepitant and fosaprepitant should be considered when selecting antiemetic therapy.

3.2 Introduction

A neurokinin-1 antagonist such as oral (PO) aprepitant or its intravenous (IV) prodrug, fosaprepitant, together with a 5-HT3 antagonist and dexamethasone, are strongly recommended for prophylaxis of chemotherapy-induced nausea and vomiting (CINV) in both adult and pediatric cancer patients receiving highly emetogenic chemotherapy.1-4 However, aprepitant and fosaprepitant are moderate5, 6 and weak inhibitors of CYP3A4,7, 8 respectively, and there is uncertainty regarding the clinical significance of potential interactions with CYP3A4 substrates.

A moderate CYP3A4 inhibitor may increase the area under the concentration versus time curve (AUC) of a victim drug by 2 to up to 5-fold and a weak CYP3A4 inhibitor may increase AUC of a victim drug by 1.25 up to 2-fold.9 CYP3A4 inhibitors may also reduce the conversion of a prodrug to its active form.10 Aprepitant or fosaprepitant may therefore influence the toxicity and the efficacy of concomitantly administered drugs. Recommendations for CINV prevention in children with cancer caution against the use of aprepitant with antineoplastic agents which are CYP3A4 substrates.3, 11 However, avoidance of aprepitant due to potential interactions with antineoplastic therapy may open patients to uncontrolled CINV.

There is, however, no comprehensive, systematic assessment of the literature describing the extent of interaction between aprepitant or fosaprepitant and other drugs. The primary objective of this systematic review was to describe the pharmacokinetic disposition of drugs co- administered with aprepitant or fosaprepitant using a standard definition of clinical significance. Our secondary objective was to describe adverse events ascribed to a drug interaction with aprepitant or fosaprepitant. The results of this systematic review will facilitate informed decision-making regarding the selection of CINV prophylaxis.

3.3 Methods

The Preferred Reporting Items in Systematic Reviews and Meta-Analyses Protocols12 and the Preferred Reporting Items in Systematic Reviews and Meta-Analyses guidelines13 were followed in conducting this systematic review. Details on the search methods can be found in Appendix B: Supplementary Tables B1-B2. The publication selection, data extraction and quality assessment procedures are presented in Appendix B (Section B).

We defined pharmacokinetic drug interactions as clinically significant according to the United States Food and Drug Administration (FDA) guidance document on drug interaction studies.14 That is, an interaction was clinically significant when: (1) the geometric mean ratio (GMR) for the comparison of a victim drug’s maximum concentration (Cmax) in the presence versus in the absence of aprepitant or fosaprepitant was greater than 1.25 or less than 0.80 or (2) the GMR for the comparison of the AUC of a victim drug in the presence versus in the absence of aprepitant or fosaprepitant was greater than 1.25 or less than 0.80. This definition was based on the GMR for Cmax or AUC of the victim drug irrespective of the associated confidence interval (CI).

A significant adverse event was defined as an event where a patient experienced discomfort, harm, or changes in a laboratory parameter that was indicative of an increased risk for harm that was highly suspected to have occurred due to co-administration of aprepitant or fosaprepitant with the patient’s other medications. In the case of comparative studies, a high suspicion of interaction was defined as a statistically significant difference in the rate of the adverse event in the presence of aprepitant or fosaprepitant versus the absence of aprepitant or fosaprepitant. The probability that the findings of case reports were a result of a drug interaction with aprepitant or fosaprepitant was determined using the Drug Interaction Probability Scale (DIPS).15 DIPS scores of 5 or greater indicate that a causal relationship between the adverse event and the drug interaction is probable or highly probable.

3.4 Results

3.4.1 Publication selection

Our literature search identified 4,377 publications. Of these, 122 were brought to full text screening and 65 met criteria to be included in the qualitative synthesis. One publication16 was excluded because it used methods that would affect the validity and generalizability of study findings. Hence, a total of 64 publications were included in the final synthesis (see Figure 3.1). Inter-screener agreement was substantial with a calculated kappa of 0.77 (95% CI: 0.65-0.88).17 There were minimal discrepancies observed during data extraction. The quality assessment of all included publications (case reports excluded) is reported in Appendix B: Supplementary Tables B3-B5. The DIPS scores of included case reports are presented in Appendix B: Supplementary Table B10.

3.4.2 Publication characteristics

Of the 64 included publications, 34 evaluated pharmacokinetic interactions (aprepitant/fosaprepitant and antineoplastic drug: 14;18-31 aprepitant/fosaprepitant and non- antineoplastic drug: 20).6, 8, 10, 32-48 Thirty-eight described adverse events potentially resulting from drug interactions with aprepitant or fosaprepitant, eight of which also evaluated for a pharmacokinetic aprepitant/fosaprepitant drug interaction (aprepitant/fosaprepitant and antineoplastic drug: 24;20, 22, 30, 49-69 aprepitant and non-antineoplastic drug: 14).10, 39, 42, 47, 48, 70-78 In all, 27 victim drugs were evaluated for pharmacokinetic interaction with aprepitant or

fosaprepitant and an adverse event was ascribed by study authors to an interaction with aprepitant or fosaprepitant for 15 victim drugs. All identified studies were conducted with adult patients. Table 3.1 summarizes the characteristics of included publications. Complete data summary tables are provided in Appendix B: Supplementary Tables B6-B9. A summary of findings are presented in Table 3.2.

3.4.3 Pharmacokinetic interactions with aprepitant or fosaprepitant

Antineoplastic Drugs

Thirteen included publications evaluated interactions between aprepitant and 10 individual antineoplastic drugs18-27, 29-31 and one publication evaluated an interaction between fosaprepitant 28 and ifosfamide. Seven included publications reported a GMR for AUC or Cmax with and without aprepitant or fosaprepitant which allowed assessment of clinical significance.24, 26-31 Of these, three interactions met criteria for clinical significance: bosutinib PO,31 cabazitaxel IV27 and cyclophosphamide IV.29

GMR for AUC and Cmax with/without aprepitant were not reported in the publications describing erlotinib (route not reported),25 ifosfamide IV,20 melphalan IV,21 pazopanib IV,22 and thiotepa IV disposition.19 However, significant differences in other pharmacokinetic parameters were reported for several of these drugs when co-administered with aprepitant. Changes in parameters indicative of reduced clearance were reported for CYP3A4 substrates in the presence of aprepitant: erlotinib (two-fold increase in the trough concentration),25 pazopanib IV (reduction of mean oral clearance by 24-37%)22 and thiotepa IV (20% lower tepa exposure).19 In addition, ifosfamide clearance was increased by approximately 60% in the presence of aprepitant.20

Non-antineoplastic Drugs

Twenty publications evaluated aprepitant or fosaprepitant interactions with 16 non-antineoplastic drugs.6, 8, 10, 32-48 Interactions between fosaprepitant and dexamethasone PO8 or midazolam PO8 and between aprepitant and dexamethasone PO,40 methylprednisolone IV,40 midazolam PO/IV,6, 43, 45 oxycodone PO35 and tolbutamide PO42 met criteria for clinical significance.

Multiple included publications evaluated aprepitant drug interactions with CYP probe drugs: midazolam PO/IV6, 39, 43, 45 and tolbutamide PO42, 43, implying effects on CYP3A4 and CYP2C9,

respectively. A significant interaction with a higher dose of aprepitant (125 mg on day 1) was consistently demonstrated.6, 39, 43, 45 When a lower dose of aprepitant of 40 mg PO day 1, followed by 25 mg PO on Days 2 and 3 was administered with midazolam PO the interaction 6 did not meet criteria for clinical significance (GMR AUC0-inf 1.22; 95%CI: 0.93-1.61 on day 1). Similarly, when a lower aprepitant dose of 40 mg was administered with tolbutamide PO, the interaction did not meet criteria for significance (GMR AUC0-inf 0.87, 90% CI: not reported on day 4).42

Study authors did not report a GMR for AUC or Cmax when describing the co-administration of the following drugs with aprepitant: alcohol IV,47 dexamethasone IV,41, 46 prednisolone PO,38 quetiapine PO,48 tacrolimus IV36 and paroxetine PO.10 However, significant differences in other pharmacokinetic parameters were reported when aprepitant was co-administered with several of these drugs. Reduced clearance or measures indicative of reduced clearance were observed for victim drugs which are CYP3A4 substrates: dexamethasone IV (reduction of dexamethasone clearance by approximately 25% and 50% in presence of aprepitant 40 mg or 125 mg, respectively41, 46), quetiapine PO (11-fold increase in plasma quetiapine concentration in presence of aprepitant48) and tacrolimus IV (43% increase in mean dose-normalized tacrolimus 36 concentration in presence of aprepitant ). In addition, the arithmetic mean AUC0-24hr and Cmax of paroxetine, a CYP2D6 substrate, were reduced by approximately 25% and 20%, respectively, in the presence of aprepitant.10

3.4.4 Adverse events ascribed to interactions with aprepitant or fosaprepitant

Most (76%; 26/34) publications reporting pharmacokinetic data did not report adverse events attributed to an aprepitant/fosaprepitant drug interaction. Eight publications did report that certain adverse events occurred more frequently with concomitant aprepitant administration. Of these, only one provided p-values47 and two were case reports.20, 48 The results of these three publications are presented with the other publications evaluating adverse events attributed to aprepitant or fosaprepitant below.

Antineoplastic Drugs

Twenty-four included publications reported adverse events attributed to co-administration of aprepitant or fosaprepitant and an antineoplastic agent (anthracyclines, bexarotene PO, dinaciclib IV, erlotinib, ifosfamide IV, and pazopanib IV).20, 22, 30, 49-66, 68 Of these, interactions between fosaprepitant and anthracyclines and aprepitant and ifosfamide IV were the suspected cause.

One prospective study56 and six retrospective studies51, 52, 57, 58, 60, 69 evaluated the incidence of phlebitis when fosaprepitant and anthracycline chemotherapy were administered via the same peripheral vein. Two of these studies compared the incidence of this adverse event in patients receiving anthracycline versus non-anthracycline chemotherapy.51, 52 In these studies, the reported odds ratios of having phlebitis with fosaprepitant and anthracycline therapy versus fosaprepitant and platinum chemotherapy were 12.95 (95% CI: 5.74 to 29.2)51 and 8.1 (95% CI: 2.0 to 31.9).52 Other studies comparing phlebitis rates with/without fosaprepitant also noted statistically significant increases in phlebitis with fosaprepitant compared to aprepitant.58, 60, 69

Thirteen publications (six retrospective studies, nine case reports and one case series) 20, 49, 50, 53- 55, 61-66, 68 evaluated neurotoxicity associated with the combination of ifosfamide and aprepitant/fosaprepitant. The interaction between aprepitant and ifosfamide was a probable cause of neurotoxicity in one of the nine case reports (DIPS: 6).20 Neurotoxicity was unlikely to be due to an interaction between ifosfamide and aprepitant/fosaprepitant in the remaining case reports (DIPS: <5).55, 61, 62, 64, 68 Results from the retrospective studies, four specifically evaluating the co-administration of ifosfamide IV with aprepitant/fosaprepitant 53, 54, 65, 66 and two evaluating general risk factors for ifosfamide-induced neurotoxicity,50, 63 did not demonstrate an increased likelihood of ifosfamide-induced neurotoxicity or encephalopathy in the presence of aprepitant/fosaprepitant.

Non-antineoplastic Drugs

Fourteen included studies10, 39, 42, 47, 48, 70-78 described potential drug interactions between aprepitant and alcohol IV, methadone PO, midazolam IV, oxycodone intranasal and PO, selective serotonin reuptake inhibitors/serotonin-norepinephrine reuptake inhibitors PO (SSRIs/SNRIs), paroxetine PO, quetiapine PO, tolbutamide PO, and warfarin PO. A probable

interaction was observed between aprepitant and alcohol IV,47 oxycodone,74 quetiapine PO,48 SSRIs/SNRIs,71 and warfarin.72, 73, 75, 78

A randomized crossover study evaluating the pharmacokinetics of alcohol IV with/without aprepitant also conducted psychomotor and cognitive function tests on its subjects. A statistically significant decline in function was found for immediate pattern recognition (p=0.043) and adaptive tracking at 7.5 h (p=0.043) when aprepitant was given concomitantly with alcohol IV. However, study authors concluded that these differences were not clinically relevant.47

A randomized crossover study examined the effects of aprepitant on the subjective and physiologic response to oxycodone in individuals with opioid abuse to identify if neurokinin-1 receptor antagonists diminish the effects of opioids related to their abuse potential.74 A statistically significant enhanced response to high oxycodone doses was noted in the presence of aprepitant with aprepitant increasing the “high” that patients experienced (PO oxycodone: p=0.39; intranasal oxycodone: p=0.007) and the estimated street value of the oxycodone (PO oxycodone: p=0.023; intranasal oxycodone: p=0.004). A lower respiratory rate (PO oxycodone: p<0.025; intranasal oxycodone: 0.005) and increased end tidal carbon dioxide (PO oxycodone: p=0.028; intranasal oxycodone: p=0.001) was also noted in the presence of aprepitant.

A case report suggested a probable interaction between quetiapine PO and aprepitant (DIPS: 6). Deep somnolence was reported when aprepitant was administered with quetiapine on days the patient was receiving chemotherapy.48

In addition, a retrospective, case-control study found that patients receiving aprepitant together with SSRIs/SNRIs PO had higher rates of National Cancer Institute-Common Toxicity Criteria version 3.0 (NCI-CTC v3.0) grade 2 or greater vomiting than a patient not receiving a SSRI or SNRI (p=0.04).71

One retrospective study and seven case reports described changes to International Normalized Ratio (INR) following the initiation of aprepitant administration in patients receiving chronic warfarin therapy.72, 73, 75-78 The retrospective study reported statistically significant increases in INR during the first week after aprepitant administration (p=0.0000149) and significant decreases two weeks after aprepitant administration (p=0.00069) versus the week prior to

aprepitant administration. The DIPS scores for four of these case reports indicated that an interaction between aprepitant and warfarin PO was probable.72, 73, 75

3.5 Discussion

Interactions between aprepitant/fosaprepitant and bosutinib PO,31 cabazitaxel IV,27 cyclophosphamide IV,29 dexamethasone PO,8, 40 methylprednisolone IV,40 midazolam PO/IV,6, 39, 43, 45 oxycodone PO35 and tolbutamide PO43 were clinically significant as defined by the FDA.14 In addition, clinical descriptions of adverse events probably or highly probably caused by co- administration of aprepitant or fosaprepitant with alcohol IV,47 anthracyclines IV,51, 52, 56-58, 60, 69 ifosfamide IV,20 midazolam IV,39 oxycodone intranasal and PO,74 quetiapine PO,48 SSRIs/SNRIs,71 and warfarin PO72, 73, 75, 78 were identified. The majority of included studies evaluated drug interactions after a single dose of aprepitant or in the dosing regimen that is approved by the FDA for the prevention of CINV, allowing the results to be translatable to clinical practice (refer to Appendix B: Supplementary Tables B6-B9 for exact dosing regimens used for specific studies).

Midazolam and tolbutamide are commonly used as probes in drug interaction studies to determine if the investigated drug is an inhibitor or inducer of CYP3A4 or CYP2C9, respectively.14 Included publications using midazolam PO support the classification of fosaprepitant as a weak CYP3A4 inhibitor8 and aprepitant as a moderate CYP3A4 inhibitor6 after the administration of the usual adult doses for CINV prevention. Delayed effects of aprepitant as a weak CYP3A4 inducer43, 45 and a weak CYP2C9 inducer have also been noted several days after the administration of aprepitant.43

Interestingly, the information required to apply the FDA definition of a significant interaction was not provided in 40% (14/35) of included pharmacokinetic studies. However, in 10 of these

14 publications, significant differences in pharmacokinetic parameters other than GMR for Cmax or AUC were reported for the following victim drugs: dexamethasone IV, erlotinib (route not reported), ifosfamide IV, quetiapine PO, pazopanib PO, paroxetine PO, tacrolimus IV, and thiotepa IV.10, 19, 20, 22, 25, 36, 41, 46, 48 Hence, there is a possibility that these interactions may be clinically significant and caution is advisable when these drugs are administered with aprepitant.

In several instances (e.g. dinaciclib IV, ifosfamide, vinorelbine IV, dolasetron PO (poor metabolizers), granisetron PO, ondansetron IV, and palonosetron IV), considerable variability in the GMR was observed and the upper or lower limit of the 90% CI exceeded the GMR threshold for clinical significance.24, 28, 30 The FDA guidance document states that a drug interaction can be considered not to be clinically significant if the 90% CI for the systemic exposure ratios fall 14 completely within 80 to 125%. Thus, cases where the 90% CIs for the GMR for AUC or Cmax fall outside this range may be a cause for concern.

Cyclophosphamide IV merits discussion since pharmacokinetic data were not reported consistently across the three included publications which describe the co-administration of aprepitant and cyclophosphamide.18, 19, 29 One of these three publications reported GMRs for

AUC and Cmax with/without aprepitant and a designation of a clinically significant interaction was made based on this information.29 Study authors for the other two publications did not report a clinically significant interaction. However, specific AUC and Cmax values were not reported in either of these publications and we were unable to draw conclusions based on our predefined definition.18, 19

Reports of the interaction between ifosfamide and aprepitant/fosaprepitant were also conflicting. While case reports20, 55, 61, 62, 68 attributed ifosfamide-induced neurotoxicity to an aprepitant- ifosfamide drug interaction, only one case report had a DIPS score that would suggest that the interaction was the probable cause (DIPS score: 6).20 The included retrospective studies did not report p-values or demonstrate a statistically significant difference in ifosfamide-induced neurotoxicity rates in the presence of aprepitant.50, 53, 54, 63, 65, 66 Furthermore, results from a randomized crossover trial reported GMRs for Cmax and AUC with/without fosaprepitant that did not meet our definition of a clinically significant interaction.28 Large, prospective studies are required to determine risk factors, including the co-administration of aprepitant or fosaprepitant, for ifosfamide-induced neurotoxicity.

All of the victim drugs that were found to have a clinically significant pharmacokinetic interaction with aprepitant or fosaprepitant were CYP3A4 or CYP2C9 substrates, consistent with what is known about the pharmacology of aprepitant and fosaprepitant. However, several CYP3A4 or CYP2C9 substrates were found not to interact to a clinically significant extent with aprepitant or fosaprepitant. Co-administration of aprepitant and CYP3A4 substrates which were

also substrates of p-glycoprotein or other efflux transporters (Appendix B: Section D) often did not lead to significant changes in pharmacokinetic disposition. We speculate that, for these drugs, elimination via alternative pathways compensates for inhibition of CYP3A4 by aprepitant/fosaprepitant and mitigates the magnitude of the interaction.

Patient-related factors may also influence the magnitude of a CYP3A4-mediated drug interaction. Patients with increased sensitivity to CYP3A4 inhibition or with reduced capacity to compensate for CYP3A4 inhibition may be at higher risk of clinically significant interactions with aprepitant or fosaprepitant. For example, patients may have reduced CYP3A4 and hepatic drug transporter activity by virtue of their age, disease states, genotype or concurrent drug therapy. Patients with inflammatory conditions or cancer may also have reduced CYP3A4 capacity.79 Young children may be particularly vulnerable since CYP3A4 concentrations steadily increase after birth and reach 30-40% of adult levels during the first year of life.80 Similarly, the activities of potentially compensatory pathways such as hepatic drug transporters p-glycoprotein and organic anion-transporting polypeptide transporters increase with age.81 However, given that CYP3A4 is the major pathway for aprepitant and fosaprepitant drug interactions, and given the ontogeny of CYP3A4, the results of this systematic review are applicable to most children, despite all of the identified studies being conducted in adults.

The strength of this systematic review is in the rigorous approach to identifying drug interaction publications and in the application of a well-recognized definition of clinical significance of drug interactions and the use of a validated tool to assess the probability of adverse events described in case reports being attributed to a drug interaction. It is limited by the small sample size of many of the included studies and lack of power to detect differences in adverse of events, as well as, at least for the non-antineoplastic victim medications, the conduct of many studies in healthy patients. This limits the external generalizability of study results and was reflected in the quality assessment of included studies. Our ability to assess the clinical significance of pharmacokinetic interactions was also limited by the proportion of reports which did not present values for GMR for AUC or Cmax. With respect to the drug interaction studies reporting adverse events, an association between the reported adverse event and co-administration of aprepitant and a victim drug could not always be confirmed as a result of multiple confounding factors. For example, many of the studies evaluating ifosfamide-induced neurotoxicity were confounded by the presence of other potential risk factors, such as plasma albumin concentrations and co-

administration of central nervous system acting agents. This ambiguity is reflected in the DIPS scores. Furthermore, the evaluation of adverse events related to drug interactions was limited to the timeframe of the studies. It is possible that changes in exposure to chemotherapy may have long-term consequences. No publication was identified evaluating the long-term effects of an aprepitant/fosaprepitant drug interaction. This is an evidence gap that requires further investigation.

3.6 Conclusion

Using systematic methods, we identified clinically significant interactions between aprepitant and fosaprepitant and 14 drugs. Administration of fosaprepitant and anthracycline antineoplastic agents via the same peripheral vein should be avoided. Dose adjustment of the victim drug or use of antiemetic agents other than aprepitant or fosaprepitant should be considered for patients receiving dexamethasone PO, methylprednisolone IV, midazolam PO/IV, oxycodone PO, or tolbutamide PO. We suggest that neurokinin-1 receptor antagonists without CYP3A4 activity be considered for patients receiving bosutinib PO, cabazitaxel IV, or cyclophosphamide IV. Although less clear, the use of antiemetics other than aprepitant/fosaprepitant may be appropriate in patients receiving erlotinib, pazopanib IV or thiotepa IV. Our findings are summarized in Table 2. Individuals with reduced capacity to metabolize drugs via CYP3A4 or other pathways, including neonates and children, may be at higher risk of experiencing clinically significant interactions due to aprepitant/fosaprepitant drug co-administration.

3.7 Acknowledgements

We thank Ms. Alanna Marson and Ms. Joanna Bielecki for guidance with the search strategy for the systematic review. We also like to thank Dr. Lusine Abrahamyan and Dr. Petros Pechlivanoglou for support and guidance. We are grateful to Dr. Masanobu Takeuchi and Dr. Hitomi Hino for their help with article translation.

Table 3.1 Study characteristics of included studies Article Aprepitant (First Median age Study Design N Population (A) or Victim Drug author, (range), years Fosaprepitant year) (F) Pharmacokinetic Drug Interaction Publications Antineoplastic Drugs Hsyu Crossover RCT 18 Healthy NR A Bosutinib PO (2015) Sarantopoulos Crossover 12 Solid malignancy 56 (32-71) A Cabazitaxel IV (2014) study Walko Cyclophosphamide Crossover RCT 18 Breast cancer 55 (38-77) A (2012) IV Patients Bubalo Cyclophosphamide Parallel RCT 22 scheduled for 46 (19-63)a A (2012) IV HSCT PK study with Cyclophosphamide De Jonge Breast cancer or historical 8 NR A IV (2005) germ cell cancer control Thiotepa IV Zhang Advanced Crossover RCT 12 52 (35-70) A Dinaciclib IV (2012) malignancy Kaneta Crossover 16 Solid tumor 67.5 (56-76) A Docetaxel IV (2014) study Nygren Crossover RCT 10 Solid malignancy NR (50-68) A Docetaxel IV (2005) Mir Case report 1 Adenocarcinoma 54 A Erlotinib (route NR) (2011) Durand Metastatic Case report 1 57 A Ifosfamide IV (2007) osteosarcoma Vadhan- Ifosfamide (route Crossover RCT 47 Malignancy NR F Raj (2015) NR) Imbs Crossover 32 Solid malignancy 56 (24-72) A Pazopanib PO (2016) study Loos Crossover Advanced solid 12 56 (NR) A Vinorelbine IV (2007) study malignancy Aprepitant arm: Egerer PK sub-study of 57.4 (40-69)a 30 Multiple myeloma A Melphalan IV (2010) parallel RCT Placebo arm: 62.1 (39-71)a Non-antineoplastic drugs G1: G1: 34 G1: Dexamethasone PO McCrea 20 (20-46)a Crossover RCT Healthy A G2: (2003) G2: G2: 31 a Methylprednisolone 10 (20-44) IV Dexamethasone G1: arm: 29.7 (18- G1: Marbury 13 Crossover RCT Healthy 45)a F Dexamethasone PO (2011) G2: Midazolam: 30.1 G2: Midazolam PO 10 (18-44)a RCT, randomized controlled trial; NR, not reported; PK, pharmacokinetic; IQR, interquartile range; C1: case 1, C2: case 2; G1: group 1; G2: group 2; SSRI, selective serotonin reuptake inhibitor; SNRI, serotonin and norepinephrine reuptake inhibitor amean age and range reported; bcharacteristics of 6 patients who experienced vascular-pain only presented by study authors; cPatients who experienced neurotoxicity

Article Aprepitant (First Median age Study Design N Population (A) or Victim Drug author, (range), years Fosaprepitant year) (F) No Japanese healthy dexamethasone: Nakade PK modeling patients and 755 62 (20-80) A Dexamethasone IV (2008) study patients with solid Dexamethasone malignancy arm: 63 (23-80) Aprepitant 125/80/80: 59.7 Japanese cancer Takahashi (47-71)a Parallel RCT 20 patients receiving A Dexamethasone IV (2011) Aprepitant chemotherapy 40/25/25: 63.6 (55-72)a G1: Blum 17 G1: 27.9 (18-44)a G1: Granisetron PO Crossover RCT Healthy A (2003) G2: G2: 34.4 (19-46)a G2: Ondansetron IV 15 Li (2006) Crossover RCT 12 Healthy NR (19-52) A Dolasetron PO Majumdar Crossover RCT 16 Healthy 30 (20-43)a A Midazolam PO (2003) Aprepitant: 29 Shadle (18-40)a Midazolam IV Parallel RCT 24 Healthy A (2004) Placebo: 29 (21- Tolbutamide PO 44)a Majumdar Crossover RCT 12 Healthy NR (20-36) A Midazolam IV (2007) Stoch Crossover Midazolam PO and 12 Healthy 34 (22-44)a A (2011) study IV Fujiwara Crossover 20 Stage IV cancer 66.5 (44-77) A Oxycodone PO (2014) study Shah Crossover RCT 12 Healthy 29.9 (NR)a A Palonosetron IV (2005) Maie Crossover 8 Lymphoma NR A Prednisolone PO (2014) study Laryngeal Verwimp- carcinoma + Hoeks Case report 1 44 A Quetiapine PO depression + (2012) anxiety Ibrahim Retrospective Reduced intensity 26 52.5 (18-68) A Tacrolimus IV (2008) review HSCT patients Aprepitant: 27 Ngo (19-37) Parallel RCT 22 Healthy A Tolbutamide PO (2009) Placebo: 26 (19- 39) Depre Parallel RCT 22 Healthy 29 (21-45)a A Warfarin PO (2005) Feuring Crossover RCT 11 Healthy 29.6 (22-45)a A Digoxin PO (2003) RCT, randomized controlled trial; NR, not reported; PK, pharmacokinetic; IQR, interquartile range; C1: case 1, C2: case 2; G1: group 1; G2: group 2; SSRI, selective serotonin reuptake inhibitor; SNRI, serotonin and norepinephrine reuptake inhibitor amean age and range reported; bcharacteristics of 6 patients who experienced vascular-pain only presented by study authors; cPatients who experienced neurotoxicity

Article Aprepitant (First Median age Study Design N Population (A) or Victim Drug author, (range), years Fosaprepitant year) (F) Ball Major depressive Parallel RCT 236 38.9 (18-65) A Paroxetine PO (2014) disorder TaBeek Crossover RCT 17 Healthy 27 (18-53)a A Alcohol IV (2013) Clinical Drug Interaction Publications (i.e. publications that did not report pharmacokinetic data) Antineoplastic Drugs Prospective Kameda Japanese, breast observational 20 48.5 (23-67)b F Anthracycline IV (2014) cancer cohort study Receiving Sato Retrospective fosaprepitant 56 50 (31-85) F Anthracycline IV (2014) review through peripheral IV line Patients Reaction group: administered 54 (IQR: 49-62) Lundburg Retrospective 150 fosaprepitant IV No reaction F Anthracycline IV (2014) review through a group: 59 (IQR: peripheral vein 51-67) Mogi Retrospective 80 Colorectal cancer NR F Anthracycline IV (2014) review Patients administered anthracycline or Fujii Retrospective Anthracycline/ 267 cisplatin based 54.3 (NR)a A/F (2015) study Platinum IV regimen not through a central line Patients administered platinum-based Platinum-based therapy not chemotherapy: containing 46.4 (22-77)a Hegerova Retrospective Anthracycline/ 180 anthracycline or Anthracycline- F (2015) review Platinum IV patients based administered chemotherapy: anthracycline- 53.3 (31-74)a cyclophosphamide chemotherapy Chemo-naïve breast cancer Aprepitant: 52 Tsuda Retrospective patients receiving (30-75) 100 A/F Anthracycline IV (2016) review anthracycline- Fosaprepitant: containing 47 (31-66) chemotherapy Ruellen Erthyrodermic Case report 1 65 A Bexarotene PO (2012) Sezary syndrome RCT, randomized controlled trial; NR, not reported; PK, pharmacokinetic; IQR, interquartile range; C1: case 1, C2: case 2; G1: group 1; G2: group 2; SSRI, selective serotonin reuptake inhibitor; SNRI, serotonin and norepinephrine reuptake inhibitor amean age and range reported; bcharacteristics of 6 patients who experienced vascular-pain only presented by study authors; cPatients who experienced neurotoxicity

Article Aprepitant (First Median age Study Design N Population (A) or Victim Drug author, (range), years Fosaprepitant year) (F) Non-small cell Sassier Erlotinib Case report 1 lung cancer and 56 A (2016) (route NR) brain metastases Aprepitant: 53 Howell Retrospective (NR)a 45 Sarcoma A Ifosfamide IV (2008) cohort study No aprepitant: 48 (NR)a Cases: 48 (NR)a Retrospective Ho (2008) 54 Sarcoma Controls: 44.8 A Ifosfamide IV case-control (NR)a Stern Retrospective Treated with 187 27 (0-78) A Ifosfamide IV (2015) study ifosfamide Treated with Retrospective Brand name: 49 Chenaf ifosfamide and Ifosfamide review of 178 (NR) A (2015) pharmacovigilance experiencing (route NR) Generic: 14 (NR) database neurotoxicity Gupta Retrospective Treated with 81 NR F Ifosfamide IV (2016) chart review ifosfamide Mahe Retrospective Treated with Ifosfamide 213 13 (1-20)c A (2016) study ifosfamide (route NR) Malignant Jarkowski Case report 1 peripheral nerve 24 A Ifosfamide IV (2008) sheath tumor McDonnell Non-Hodgkin Ifosfamide Case report 1 66 A (2012) lymphoma (route NR) C1: Ovarian malignant mixed Shindorf C1: 67 Case reports 2 mesodermal tumor A Ifosfamide IV (2013) (MMMT), C2: 41 C2: uterine MMMT C1: uterine Sejourne leiomyosarcoma C1: 39 Case reports 2 A Ifosfamide IV (2014) C2: pleiomorphic C2: 75 rhabdomyosarcoma Ifosfamide- NR (8 children: Barthelemi Ifosfamide Case series 10 induced 2-15; 2 adults: A (2015) (route NR) encephalopathy 51 and 80) C1: osteosarcoma with previous Sunela history of breast C1: 59 Case reports 2 A Ifosfamide IV (2016) cancer C2: 65 C2: metastatic sarcoma Non-antineoplastic Drugs Walsh Oxycodone Crossover RCT 8 Illicit opioid users 32.3 (NR)a A (2013) intranasal and PO RCT, randomized controlled trial; NR, not reported; PK, pharmacokinetic; IQR, interquartile range; C1: case 1, C2: case 2; G1: group 1; G2: group 2; SSRI, selective serotonin reuptake inhibitor; SNRI, serotonin and norepinephrine reuptake inhibitor amean age and range reported; bcharacteristics of 6 patients who experienced vascular-pain only presented by study authors; cPatients who experienced neurotoxicity

Article Aprepitant (First Median age Study Design N Population (A) or Victim Drug author, (range), years Fosaprepitant year) (F) Methadone- maintained Jones Parallel RCT 15 patients with 47.3 (31-59)a A Methadone PO (2013) opioid abuse and dependence Chemotherapy Retrospective Mir naïve patients SSRI case-control 44 59 (34-78) A (2012) receiving SSRI or (route NR) study SNRI Patients receiving Takaki Retrospective 14 anticancer 59 (33-78)a A Warfarin PO (2016) study therapy C1: ovarian malignancy + disseminated intravascular Yano coagulation C1: 50 Case reports 2 A Warfarin PO (2011) C2: peritoneal C2: 43 recurrence and liver metastasis of uterine cervical adenocarcinoma C1: small cell lung cancer + atrial fibrillation, Japanese C2: endometrial Ohno carcinoma + C1: 60 Case reports 2 A Warfarin PO (2014) pulmonary C2: 47 thrombosis and deep vein thrombosis, Japanese Squamous cell carcinoma Nakano including Case report 1 64 A Warfarin PO (2015) urothelial carcinoma + deep vein thrombosis Clear cell Inagaki carcinoma + Warfarin Case report 1 63 A (2015) pulmonary (route NR) embolism Rhabdomyosarcoma Okada and occlusion of left Case report 1 15 A Warfarin PO (2016) middle cerebral artery, Japanese RCT, randomized controlled trial; NR, not reported; PK, pharmacokinetic; IQR, interquartile range; C1: case 1, C2: case 2; G1: group 1; G2: group 2; SSRI, selective serotonin reuptake inhibitor; SNRI, serotonin and norepinephrine reuptake inhibitor amean age and range reported; bcharacteristics of 6 patients who experienced vascular-pain only presented by study authors; cPatients who experienced neurotoxicity

Table 3.2 Summary of findings regarding pharmacokinetic interactions with aprepitant/fosaprepitant Drugs evaluated for pharmacokinetic interactions with aprepitant Clinically significant interactiona: Antineoplastic agents: bosutinib PO cabazitaxel IV cyclophosphamide IV Non-antineoplastic agents: dexamethasone PO methylprednisolone IV midazolam IV and PO oxycodone PO tolbutamide PO Possibly significant interactionb: Antineoplastic agents: erlotinib (route not reported) ifosfamide IV pazopanib PO thiotepa IV Non-antineoplastic agents: dexamethasone IV paroxetine PO quetiapine PO tacrolimus IV Possibly no clinically significant Antineoplastic agents: melphalan IV interactionc: Non-antineoplastic agents: alcohol IV prednisolone PO No clinically significant interactiond: Antineoplastic agents: dinaciclib IV docetaxel IV vinorelbine IV Non-antineoplastic agents: digoxin PO dolasetron PO granisetron PO ondansetron IV palonosetron IV warfarin PO Drugs evaluated for pharmacokinetic interactions with fosaprepitant Clinically significant interactiona: Antineoplastic agents: none evaluated Non-antineoplastic agents: dexamethasone PO midazolam PO No clinically significant interactionc : Antineoplastic agents: ifosfamide IV Non-antineoplastic agents: none evaluated a b met pre-defined definition of clinical significance; significant change in pharmacokinetic parameters observed; GMR of Cmax or c d AUC not provided; no significant change in pharmacokinetic parameters observed; GMR of Cmax or AUC not provided; did not meet pre-defined definition of clinical significance

Figure 3.1 Study identification flow diagram

3.8 References

1. Basch E, Prestrud AA, Hesketh PJ, Kris MG, Feyer PC, Somerfield MR, et al. Antiemetics: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol. 2011;29(31):4189-98.

2. Roila F, Herrstedt J, Aapro M, Gralla RJ, Einhorn LH, Ballatori E, et al. Guideline update for MASCC and ESMO in the prevention of chemotherapy- and radiotherapy-induced nausea and vomiting: results of the Perugia consensus conference. Ann Oncol. 2010;21 Suppl 5:v232- 43.

3. Dupuis LL, Boodhan S, Holdsworth M, Robinson PD, Hain R, Portwine C, et al. Guideline for the prevention of acute nausea and vomiting due to antineoplastic medication in pediatric cancer patients. Pediatr Blood Cancer. 2013;60(7):1073-82.

4. Kang HJ, Loftus S, Taylor A, DiCristina C, Green S, Zwaan CM. Aprepitant for the prevention of chemotherapy-induced nausea and vomiting in children: a randomised, double- blind, phase 3 trial. Lancet Oncol. 2015;16(4):385-94.

5. Merck Canada Inc. Product Monograph Emend [Internet]. Kirkland (QC): Health Canada Drug Product Database, 2014 January [Cited 2016 October 10]. Available from: https://health- products.canada.ca/dpd-bdpp/info.do?code=78411&lang=en.

6. Majumdar AK, McCrea JB, Panebianco DL, Hesney M, Dru J, Constanzer M, et al. Effects of aprepitant on cytochrome P450 3A4 activity using midazolam as a probe. Clinical Pharmacology and Therapeutics. 2003;74(2):150-6.

7. Merck Canada Inc. Product Monograph Emend IV [Internet]. Kirkland (QC): Health Canada Drug Product Database, 2014 January [Cited 2016 October 10]. Available from: https://health-products.canada.ca/dpd-bdpp/info.do?code=84835&lang=en

8. Marbury TC, Ngo PL, Shadle CR, Jin B, Panebianco D, Caro L, et al. Pharmacokinetics of oral dexamethasone and midazolam when administered with single-dose intravenous 150 mg fosaprepitant in healthy adult subjects. Journal of Clinical Pharmacology. 2011;51(12):1712-20.

9. U.S. Food and Drug Administration. Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers [Internet]. Silver Spring (MD): U.S. Food and Drug Administration; 2017 November 14 [cited 2016 October 11]. Available from: http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractio nsLabeling/ucm093664.htm

10. Ball WA, Snavely DB, Hargreaves RJ, Szegedi A, Lines C, Reines SA. Addition of an NK1 receptor antagonist to an SSRI did not enhance the antidepressant effects of SSRI monotherapy: results from a randomized clinical trial in patients with major depressive disorder. Human Psychopharmacology. 2014;29(6):568-77.

11. MASCC, Multinational Association for Supportive Care in Cancer™. MASCC/ESMO Antiemetic Guideline [Internet]. 2016 [cited 11 October 2016]. Available from: http://www.mascc.org/antiemetic-guidelines 70

12. Shamseer L, Moher D, Clarke M, Ghersi D, Liberati A, Petticrew M, et al. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015: elaboration and explanation. BMJ. 2015;349:g7647.

13. Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gotzsche PC, Ioannidis JP, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. PLoS Med. 2009;6(7):e1000100.

14. U.S. Food and Drug Administration. Drug Interaction Studies — Study Design, Data Analysis, Implications for Dosing, and Labeling Recommendations [Internet]. Silver Spring (MD): U.S. Food and Drug Administration; 2012 [cited 11 October 2016]. Available from: http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractio nsLabeling/ucm093606.htm.

15. Horn JR, Hansten PD, Chan LN. Proposal for a new tool to evaluate drug interaction cases. The Annals of pharmacotherapy. 2007;41(4):674-80.

16. Shayani S, Palmer JM, Stiller T, Chan H, Keuylian S, Parker P, et al. Aprepitant (Emend) significantly increases sirolimus levels in patients undergoing allogeneic hematopoietic SCT. Bone Marrow Transplantation. 2012;47(2):291-3.

17. McHugh ML. Interrater reliability: the kappa statistic. Biochemia medica. 2012;22(3):276-82.

18. Bubalo JS, Cherala G, McCune JS, Munar MY, Tse S, Maziarz R. Aprepitant pharmacokinetics and assessing the impact of aprepitant on cyclophosphamide metabolism in cancer patients undergoing hematopoietic stem cell transplantation. Journal of Clinical Pharmacology. 2012;52(4):586-94.

19. De Jonge ME, Huitema ADR, Holtkamp MJ, Van Dam SM, Beijnen JH, Rodenhuis S. Aprepitant inhibits cyclophosphamide bioactivation and thiotepa metabolism. Cancer Chemoth Pharm. 2005;56(4):370-8.

20. Durand JP, Gourmel B, Mir O, Goldwasser F. Antiemetic neurokinin-1 antagonist aprepitant and ifosfamide-induced encephalopathy. Ann Oncol. 2007;18(4):808-9.

21. Egerer G, Eisenlohr K, Gronkowski M, Burhenne J, Riedel KD, Mikus G. The NK receptor antagonist aprepitant does not alter the pharmacokinetics of high-dose melphalan chemotherapy in patients with multiple myeloma. Br J Clin Pharmacol. 2010;70(6):903-7.

22. Imbs DC, Dieras V, Bachelot T, Campone M, Isambert N, Joly F, et al. Pharmacokinetic interaction between pazopanib and cisplatin regimen. Cancer Chemotherapy & Pharmacology. 2016;77(2):385-92.

23. Kaneta T, Fujita KI, Akiyama Y, Kawara K, Sunakawa Y, Kawachi A, et al. No pharmacokinetic alteration of docetaxel following coadministration of aprepitant 3 h before docetaxel infusion. Cancer Chemoth Pharm. 2014;74(3):539-47.

24. Loos WJ, De Wit R, Freedman SJ, Van Dyck K, Gambale JJ, Li S, et al. Aprepitant when added to a standard antiemetic regimen consisting of ondansetron and dexamethasone does not affect vinorelbine pharmacokinetics in cancer patients. Cancer Chemoth Pharm. 2007;59(3):407- 12.

25. Mir O, Blanchet B, Goldwasser F. More on aprepitant for erlotinib-induced pruritus. New Engl J Med. 2011;364(5):487.

26. Nygren P, Hande K, Petty KJ, Fedgchin M, Van Dyck K, Majumdar A, et al. Lack of effect of aprepitant on the pharmacokinetics of docetaxel in cancer patients. Cancer Chemotherapy and Pharmacology. 2005;55(6):609-16.

27. Sarantopoulos J, Mita AC, Wade JL, Morris JC, Rixe O, Mita MM, et al. Phase i study of cabazitaxel plus cisplatin in patients with advanced solid tumors: Study to evaluate the impact of cytochrome P450 3A inhibitors (aprepitant, ketoconazole) or inducers (rifampin) on the pharmacokinetics of cabazitaxel. Cancer Chemoth Pharm. 2014;74(6):1113-24.

28. Vadhan-Raj S, Zhou X, Spasojevic I, Ravi V, Araujo D, Somaiah N, et al. Randomised, cross over study of fosaprepitant (single dose vs two doses) for nausea and vomiting in Sarcoma patients receiving multi-day chemotherapy. Support Care Cancer. 2015;1):S131-S2.

29. Walko CM, Combest AJ, Spasojevic I, Yu AYC, Bhushan S, Hull JH, et al. The effect of aprepitant and race on the pharmacokinetics of cyclophosphamide in breast cancer patients. Cancer Chemoth Pharm. 2012;69(5):1189-96.

30. Zhang D, Mita M, Shapiro GI, Poon J, Small K, Tzontcheva A, et al. Effect of aprepitant on the pharmacokinetics of the cyclin-dependent kinase inhibitor dinaciclib in patients with advanced malignancies. Cancer Chemoth Pharm. 2012;70(6):891-8.

31. Hsyu PH, Matschke K, Soriano-Pignataro D. An open-label, randomized, 2-period crossover study to evaluate the effect of a single oral dose of aprepitant, a moderate CYP3A inhibitor on bosutinib administered orally to healthy subjects. 2015 AAPS Annual Meeting and Exposition; October 25-29, 2015; Orlando, USA.

32. Blum RA, Majumdar A, McCrea J, Busillo J, Orlowski LH, Panebianco D, et al. Effects of aprepitant on the pharmacokinetics of ondansetron and granisetron in healthy subjects. Clinical Therapeutics. 2003;25(5):1407-19.

33. Depre M, Van Hecken A, Oeyen M, De Lepeleire I, Laethem T, Rothenberg P, et al. Effect of aprepitant on the pharmacokinetics and pharmacodynamics of warfarin. European Journal of Clinical Pharmacology. 2005;61(5-6):341-6.

34. Feuring M, Lee Y, Orlowski LH, Michiels N, De Smet M, Majumdar AK, et al. Lack of effect of aprepitant on digoxin pharmacokinetics in healthy subjects. Journal of Clinical Pharmacology. 2003;43(8):912-7.

35. Fujiwara Y, Toyoda M, Chayahara N, Kiyota N, Shimada T, Imamura Y, et al. Effects of aprepitant on the pharmacokinetics of controlled-release oral oxycodone in cancer patients. PloS one. 2014;9(8):e104215.

36. Ibrahim RB, Abidi MH, Ayash LJ, Cronin SM, Cadotte C, Mulawa J, et al. Effect of aprepitant on intravenous tacrolimus disposition in reduced intensity hematopoietic stem cell transplantation.[Erratum appears in J Oncol Pharm Pract. 2008 Dec;14(4):233]. J Oncol Pharm Pract. 2008;14(3):113-21.

37. Li SX, Pequignot E, Panebianco D, Lupinacci P, Majumdar A, Rosen L, et al. Lack of effect of aprepitant on hydrodolasetron pharmacokinetics in CYP2D6 extensive and poor metabolizers. Journal of Clinical Pharmacology. 2006;46(7):792-801.

38. Maie K, Okoshi Y, Takaiwa N, Kurita N, Hasegawa Y, Homma M, et al. Aprepitant does not alter prednisolone pharmacokinetics in patients treated with R-CHOP. Ann Oncol. 2014;25(1):298-9.

39. Majumdar AK, Yan KX, Selverian DV, Barlas S, Constanzer M, Dru J, et al. Effect of aprepitant on the pharmacokinetics of intravenous midazolam. Journal of Clinical Pharmacology. 2007;47(6):744-50.

40. McCrea JB, Majumdar AK, Goldberg MR, Iwamoto M, Gargano C, Panebianco DL, et al. Effects of the neurokinin1 receptor antagonist aprepitant on the pharmacokinetics of dexamethasone and methylprednisolone. Clinical Pharmacology and Therapeutics. 2003;74(1):17-24.

41. Nakade S, Ohno T, Kitagawa J, Hashimoto Y, Katayama M, Awata H, et al. Population pharmacokinetics of aprepitant and dexamethasone in the prevention of chemotherapy-induced nausea and vomiting. Cancer Chemotherapy and Pharmacology. 2008;63(1):75-83.

42. Ngo PL, Shadle CR, Murphy MG, Jin B, Panebianco DL, Evans JK, et al. Effect of aprepitant 40 mg on cytochrome P-450 2C9 activity: A randomized, double-blind, placebo- controlled, parallel-group study in healthy young adults. Journal of Applied Research. 2009;9(4):123-31.

43. Shadle CR, Lee Y, Majumdar AK, Petty KJ, Gargano C, Bradstreet TE, et al. Evaluation of Potential Inductive Effects of Aprepitant on Cytochrome P450 3A4 and 2C9 Activity. Journal of Clinical Pharmacology. 2004;44(3):215-23.

44. Shah AK, Hunt TL, Gallagher SC, Cullen Jr MT. Pharmacokinetics of palonosetron in combination with aprepitant in healthy volunteers. Current Medical Research and Opinion. 2005;21(4):595-601.

45. Stoch SA, Gargano C, Valentine J, Braun MP, Murphy MG, Fedgchin M, et al. Double- blind crossover study to assess potential differences in cytochrome P450 3A4 activity in healthy subjects receiving ondansetron plus dexamethasone, with and without aprepitant. Cancer Chemotherapy and Pharmacology. 2011;67(6):1313-21.

46. Takahashi T, Nakamura Y, Tsuya A, Murakami H, Endo M, Yamamoto N. Pharmacokinetics of aprepitant and dexamethasone after administration of chemotherapeutic agents and effects of plasma substance P concentration on chemotherapy-induced nausea and vomiting in Japanese cancer patients. Cancer Chemoth Pharm. 2011;68(3):653-9.

47. Te Beek ET, Tatosian D, Majumdar A, Selverian D, Klaassen ES, Petty KJ, et al. Placebo- and amitriptyline-controlled evaluation of central nervous system effects of the NK1 receptor antagonist aprepitant and intravenous alcohol infusion at pseudo-steady state. Journal of Clinical Pharmacology. 2013;53(8):846-56.

48. Verwimp-Hoeks MPA, Van Herpen CML, Burger DM. Aprepitant quetiapine: A clinically significant drug interaction in a patient treated for head and neck cancer. Ann Oncol. 2012;23(3):801-2.

49. Barthelemi L, Bara E, Descoeur J, Hillaire-Buys D, Mathieu O, Sirvent N. Ifosfamide- induced encephalopathy: Symptoms and efficacy of methylene blue (MB) in the treatment and prevention of this adverse effect. Fundamental and Clinical Pharmacology. 2015;29:24.

50. Chenaf C, Barthelemi L, Descoeur J, Fournier-Choma C, Hillaire-Buys D, Zenut M. Ifosfamide-induced neurotoxicity, brand-name versus generic formulation: A review of the French Pharmacovigilance Database. Fundamental and Clinical Pharmacology. 2015;29:40.

51. Fujii T, Nishimura N, Urayama KY, Kanai H, Ishimaru H, Kawano J, et al. Differential impact of fosaprepitant on infusion site adverse events between cisplatin- and anthracycline- based chemotherapy regimens. Anticancer Research. 2015;35(1):379-84.

52. Hegerova LT, Leal AD, Grendahl DC, Seisler DK, Sorgatz KM, Anderson KJ, et al. An analysis of fosaprepitant-induced venous toxicity in patients receiving highly emetogenic chemotherapy. Support Care Cancer. 2015;23(1):55-9.

53. Ho H, Yuen C. Letter to the editor. J Oncol Pharm Pract. 2010;16(2):137-8.

54. Howell JE, Szabatura AH, Hatfield Seung A, Nesbit SA. Characterization of the occurrence of ifosfamide-induced neurotoxicity with concomitant aprepitant. J Oncol Pharm Pract. 2008;14(3):157-62.

55. Jarkowski IA. Possible contribution of aprepitant to ifosfamide-induced neurotoxicity. Am J Health-Syst Pharm. 2008;65(23):2229-31.

56. Kameda K, Kiba T, Ogawa Y, Kimoto S, Kajiume S, Okada Y, et al. [Effect of dexamethasone on vascular pain caused by the administration of fosaprepitant dimeglumine and epirubicin hydrochloride in patients with primary breast cancer]. Gan to kagaku ryoho Cancer & chemotherapy. 2014;41(10):1255-7.

57. Lundberg JD, Crawford BS, Phillips G, Berger MJ, Wesolowski R. Incidence of infusion-site reactions associated with peripheral intravenous administration of fosaprepitant. Support Care Cancer. 2014;22(6):1461-6.

58. Mogi A, Takamatsu Y, Fukuda M, Oda M, Kuboda T, Nishida M, et al. Evaluation of phlebitis attribute to chemotherapy in colorectal cancer patients of our institution. Ann Oncol. 2014;25:v67.

59. Ruellan AL, Dreno B, Saint-Jean M, Joyau C, Mahe J, Veyrac G, et al. Interaction between Bexarotene and Aprepitant: The First Case of Death. Drug Saf. 2012;35(10):897-.

60. Sato Y, Kondo M, Inagaki A, Komatsu H, Okada C, Naruse K, et al. Highly frequent and enhanced injection site reaction induced by peripheral venous injection of fosaprepitant in anthracycline-treated patients. J. 2014;5(5):390-7.

61. Sejourne A, Noal S, Boone M, Bihan C, Sassier M, Andrejak M, et al. Two cases of fatal encephalopathy related to ifosfamide: An adverse role of aprepitant? Case Reports in Oncology. 2014;7(3):669-72.

62. Shindorf ML, Manahan KJ, Geisler JP. The interaction of ifosfamide and aprepitant in gynecologic malignancies. Gynecologic Oncology Case Reports. 2013;6:34-5.

63. Stern N, Lervat C, Sophie Defachelles A, Ryckewaert T, Marliot G, Sakji I, et al. Risk factors for ifosfamide-related encephalopathy (IRE) in sarcoma (S) patients (pts). Journal of Clinical Oncology Conference. 2015;33(15 SUPPL. 1).

64. McDonnell AM, Rybak I, Wadleigh M, Fisher DC. Suspected serotonin syndrome in a patient being treated with methylene blue for ifosfamide encephalopathy. J Oncol Pharm Pract. 2012;18(4):436-9.

65. Gupta R, Hartwell R, Khanal R, Chen J, Hayes GL, Perez A, et al. Fosaprepitant as a risk factor for ifosfamide induced encephalopathy: A single institution experience. Journal of Clinical Oncology Conference. 2016;34(no pagination).

66. Mahe J, Corradini N, Chauvin C, Joyau C, Ruellan AL, Veyrac G, et al. Retrospective study on determinants of ifosfamide induced neurotoxicity. Drug Saf. 2015;38 (10):1001.

67. Sassier M, Peyro-Saint-Paul L, Clarisse B, Leconte A, Coquerel A, Alexandre J, et al. Chemotherapy (platinum and pemetrexed) in combination with erlotinib in non-small cell lung cancer induces major gastrointestinal toxicity: two case reports from the FLARE/GFPC 03-2013 study. Journal of Clinical Pharmacy and Therapeutics. 2016;41(4):447-8.

68. Sunela K, Barlund M. Treatment and prevention of iphosphamide-induced encephalopathy. [Finnish]. Duodecim; laaketieteellinen aikakauskirja. 2016;132(4):314-7.

69. Tsuda T, Kyomori C, Mizukami T, Taniyama T, Izawa N, Horie Y, et al. Infusion site adverse events in breast cancer patients receiving highly emetic chemotherapy with prophylactic anti-emetic treatment with aprepitant and fosaprepitant: A retrospective comparison. Molecular and Clinical Oncology. 2016;4(4):603-6.

70. Jones JD, Speer T, Comer SD, Ross S, Rotrosen J, Reid MS. Opioid-like effects of the neurokinin 1 antagonist aprepitant in patients maintained on and briefly withdrawn from methadone. Am J Drug Alcohol Abuse. 2013;39(2):86-91.

71. Mir O, Durand JP, Boudou-Rouquette P, Giroux J, Coriat R, Cessot A, et al. Interaction between serotonin reuptake inhibitors, 5-HT3 antagonists, and NK1 antagonists in cancer patients receiving highly emetogenic chemotherapy: A case-control study. Support Care Cancer. 2012;20(9):2235-9.

72. Nakano K, Ushijima K, Ando H, Fujimura A, Morita T. Enhancement of anticoagulant effect of warfarin in a bladder cancer patient during treatment with gemcitabine and cisplatin. International Cancer Conference Journal. 2015;4(4):254-7.

73. Ohno Y, Yamada M, Yamaguchi R, Hisaka A, Suzuki H. Persistent drug interaction between aprepitant and warfarin in patients receiving anticancer chemotherapy. International Journal of Clinical Pharmacy. 2014;36(6):1134-7.

74. Walsh SL, Heilig M, Nuzzo PA, Henderson P, Lofwall MR. Effects of the NK1 antagonist, aprepitant, on response to oral and intranasal oxycodone in prescription opioid abusers. Addiction biology. 2013;18(2):332-43.

75. Yano R, Kurokawa T, Tsuyoshi H, Shinagawa A, Sawamura Y, Matsunaga A, et al. Transient elevation of international normalized ratio during cisplatin-based chemotherapy in patients who are taking warfarin. Annals of Pharmacotherapy. 2011;45(10):e55.

76. Inagaki Y, Suzuki T, Saeki S, Tsushita N, Sakai T, Kato T, et al. Construction of the system of treatment for deep venous thrombosis with malignant tumor in Anjo Kosei Hospital. Ann Oncol. 2015;26:vii139-vii40.

77. Okada N, Watanabe H, Kagami S, Ishizawa K. Ifosfamide and etoposide chemotherapy may interact with warfarin, enhancing the warfarininduced anticoagulant response. International Journal of Clinical Pharmacology & Therapeutics. 2016;54(1):58-61.

78. Takaki J, Ohno Y, Yamada M, Yamaguchi Y, Hisaka A, Suzuki H. Assessment of Drug- Drug Interaction between Warfarin and Aprepitant and Its Effects on PT-INR of Patients Receiving Anticancer Chemotherapy. Biological and Pharmaceutical Bulletin. 2016;39(5):863-8.

79. Kacevska M, Robertson GR, Clarke SJ, Liddle C. Inflammation and CYP3A4-mediated drug metabolism in advanced cancer: impact and implications for chemotherapeutic drug dosing. Expert Opin Drug Metab Toxicol. 2008;4(2):137-49.

80. de Wildt SN, Kearns GL, Leeder JS, van den Anker JN. Cytochrome P450 3A: ontogeny and drug disposition. Clin Pharmacokinet. 1999;37(6):485-505.

81. Prasad B, Gaeadigk A, Vrana M, Gaedigk R, Leeder J, Salphati L, et al. Ontogeny of hepatic drug transporters as quantified by LC-MS/MS proteomics. Clinical Pharmacology & Therapeutics. 2016;100(4):362-70.

Chapter 4 Relative Bioavailability of an Extemporaneous Oral Suspension of Aprepitant in Healthy Adult Volunteers

The contents of this chapter will be submitted for publication consideration.

All of the authors have contributed to the review of the study protocol and manuscript preparation. Dr. Paul Nathan acted as the Qualified Investigator and primary study physician.

I was involved with protocol development, the research ethics approval process, Health Canada approval process, recruitment, coordinating and monitoring study day activities, follow-up, data collection, data analysis and manuscript preparation.

« Heading styles 1-9 for thesis body: Heading 1 »

4.1 Abstract

Purpose: Use of aprepitant in patients unable to swallow capsules is hindered by the lack of a commercially available aprepitant oral liquid formulation in many jurisdictions including Canada. A stable, extemporaneous oral suspension can be prepared using commercially available capsules. We aimed to determine the bioavailability of this aprepitant oral suspension relative to the capsule.

Methods: This two-period, crossover study enrolled 17 healthy adult volunteers. Volunteers received a single 125 mg aprepitant dose during each study period. Order of formulation presentation (capsule vs suspension first) was randomized. Thirteen blood samples were collected over a 48-hour period. Aprepitant plasma concentrations were determined using liquid chromatography-mass spectroscopy. Relative bioavailability was defined as the geometric least squares mean ratio for area under the concentration versus time curve (AUC) from time zero to infinity of the aprepitant suspension versus the capsule. Bioequivalence, defined as per Health Canada guidelines, was assessed as a secondary aim.

Results: Relative bioavailability of the aprepitant oral suspension was 82.3% (90% CI: 69.09- 98.00%). Bioequivalence was not established: geometric least squares mean ratios (suspension/capsule) for AUC time zero to 48 hours and maximum concentration were 87.8% (90% CI: 75.48-102.16%) and 86.1% (90% CI: 75.59-98.16%), respectively. No serious adverse events were observed.

Conclusion: The aprepitant oral suspension was well-tolerated and, with a relative bioavailability of 82.3%, well-absorbed relative to the capsule. Though the aprepitant oral suspension did not demonstrate bioequivalence to the oral capsule, its clinical use in adult and pediatric patients unable to swallow capsules is acceptable.

4.2 Introduction

Aprepitant, a neurokinin-1 (NK1) receptor antagonist, in combination with a 5- hydroxytryptamine 3 (5-HT3) receptor antagonist and dexamethasone has been the standard of care for the prevention of acute chemotherapy-induced nausea and vomiting (CINV) in adults for over a decade.1 In contrast, the evidence to support the use of aprepitant in children and 78

adolescents is more recent. A large pediatric placebo-controlled randomized trial, published in

2015, demonstrated the efficacy of aprepitant when given in combination with a 5-HT3 receptor antagonist with or without dexamethasone for the prevention of acute CINV in children aged 6 months to 17 years.2 In light of this pivotal trial and other pediatric studies also demonstrating the benefit of using aprepitant for CINV prophylaxis,2-6 clinical practice guidelines for the prevention of acute CINV in children were updated to recommend the use of aprepitant in combination with a 5-HT3 receptor antagonist and dexamethasone as first-line CINV prophylaxis 7-9 in children receiving highly emetogenic chemotherapy. Aprepitant is currently the only NK1 receptor antagonist recommended for use in children by clinical practice guidelines.7-9 Fosaprepitant, the IV prodrug form of aprepitant, is currently not indicated or recommended for pediatric use.

The United States Food and Drug Administration (FDA) and European Medicines Agency (EMA) have approved the use of aprepitant in children for the prevention of CINV.10, 11 In addition, both agencies also approved the marketing of a 25 mg/mL aprepitant oral suspension in their jurisdictions.10, 11 However, this oral suspension is not commercially available in Canada and other countries. The lack of a readily available aprepitant oral liquid formulation presents a barrier to this effective medication for adult and pediatric cancer patients unable to swallow capsules in these jurisdictions. To overcome this barrier, an extemporaneous aprepitant oral suspension can be made using the commercially available aprepitant capsules.12 This formulation is stable under refrigeration at 4°C for up to 90 days. This extemporaneously prepared oral suspension is currently used by many institutions, including The Hospital for Sick Children, Toronto, Canada (SickKids). Aprepitant has low water solubility and is poorly absorbed.13 A nanoparticle formulation of aprepitant was therefore developed to help improve its oral bioavailability.13 The currently marketed 125 mg aprepitant capsules are composed of aprepitant nanoparticle coated beads, 13 and, in adults, have an absolute bioavailability of 59% (95% confidence interval (CI): 53% to 65%) relative to an intravenous 2 mg stable isotope-labelled aprepitant dose.14 It is not known if crushing and trituration of the capsule contents, as required to compound the oral suspension, will influence aprepitant’s absorption.15 While increased systemic exposure to aprepitant is unlikely to cause harm, inadequate systemic exposure to aprepitant may result in sub-optimal CINV control.

The aim of this study was to describe the bioavailability of an extemporaneously prepared oral suspension12 relative to the capsule. The assessment of bioequivalence between the suspension and the capsule was assessed as a secondary aim. Having this knowledge will allow prescribers to make decisions about prescribing and dispensing this extemporaneous aprepitant oral suspension with more confidence.

4.3 Materials and Methods

This was a prospective, randomized, two-period crossover study. It was approved by Health Canada and the Research Ethics Boards at SickKids and The University of Toronto, Toronto, Canada. The study was conducted at the Clinical Research Centre at SickKids. Informed consent was obtained from all study volunteers.

4.3.1 Eligibility

Study volunteers were 18 to 55 years of age, non-smokers, and healthy as determined by a physician (PN) (i.e. had no clinically significant diseases captured in their medical history, laboratory tests and/or physical examination). Hepatic and renal function were determined to be normal as per plasma alanine aminotransferase, aspartate aminotransferase, conjugated and unconjugated bilirubin, creatinine and urea concentrations. In addition, volunteers had a body mass index within 18.5 to 30 kg/m2, systolic blood pressure between 90-140 mmHg, diastolic blood pressure between 60-90 mmHg, heart rate between 60-100 beats per minute and were able to swallow whole aprepitant capsules. Female volunteers of childbearing potential were also either sexually inactive (abstinent) or used an acceptable method of birth control for 15 days prior to their first study dose, throughout the study and at least 30 days after their last aprepitant dose. Potential study volunteers were excluded if they had a clinically significant illness or surgery within 8 weeks prior to their aprepitant dose, used recreational drugs, prescription medications or natural health products within 7 days or 5 half-lives (whichever was longer) prior to administration of the first dose of aprepitant, had a history of alcohol abuse within the last 6 months, a severe mental disorder, were pregnant or breastfeeding, had donated 50 mL to 499 mL of whole blood within 30 days, or more than 499 mL of whole blood within 56 days prior to drug administration, or if they consumed grapefruit or grapefruit products within 7 days of each study period.

4.3.2 Aprepitant Dosing

A single 125 mg aprepitant dose was administered orally to study volunteers during each study period, once as the aprepitant capsule and once as the extemporaneously prepared 20 mg/mL aprepitant oral suspension. The directions for making the oral suspension are presented in Appendix C (Section A). The oral suspension was compounded by SickKids’ Research Support Pharmacy using the published formulation.12 Each aprepitant dose was taken with 150 mL of water. The order of formulation presentation (capsule versus suspension first) was randomized in blocks of 4 in a 1:1 ratio. The randomization was not known to the study team until the morning of the first study period (after the volunteer signed consent). The washout period between aprepitant doses was at least 6 days and no more than 6 weeks.

Volunteers fasted for 8 hours prior to each aprepitant dose, with the exception of water, which was permitted up until 1 hour prior to their dose. After administration of each aprepitant dose, volunteers continued to fast for 4 hours at which time they ate a standardized meal. All volunteers remained on-site for the first 4 hours post-aprepitant dose.

4.3.3 Aprepitant Blood Sample Collection

All blood samples were collected into lithium heparin tubes via a peripheral venous access device or venipuncture. Blood samples were collected just prior to each aprepitant dose (time zero) and 0.5, 1, 2, 3, 4, 5, 6, 8, 10-12, 24, 32-36 and 48 hours post-dose during each study period. A 48-hour time period was chosen to ensure that at least three elimination half-lives of aprepitant (range: 9 to 13 hours)11 was captured as per the Health Canada Guidance Document for Conduct and Analysis of Comparative Bioavailability Studies.16 Sampling times could be adjusted by up to 0.5 hours during the first 5 hours, and by up to 2 hours for the sampling times from 6 to 48 hours post-aprepitant dose.

4.3.4 Adverse Event Monitoring

Vital signs (oral temperature, heart rate, blood pressure) were monitored pre-aprepitant dose and 4, 24 and 48 hours post-aprepitant dose. Study volunteers were asked about potential adverse events each day when blood was collected and by telephone 7 to 9 days after each aprepitant dose. Volunteers were also asked to report any adverse events that may have occured 30 days

post-aprepitant dose. All adverse events were assessed for the likelihood of being attributed to aprepitant (definitely, probably, possibly, unlikely, or unrelated) by the qualified investigator (PN) as per SickKids’ adverse event reporting guidelines and graded for their severity using Common Terminology Criteria for Adverse Events (CTCAE) v4.03.17

4.3.5 Aprepitant Plasma Concentration Determination

Aprepitant was quantified by liquid chromatography tandem mass-spectroscopy at the Analytical Facility for Bioactive Molecules, SickKids Research Institute. The aprepitant assay was developed based on a previously published study.18 The lower and upper limits of quantification were 1 ng/mL and 2000 ng/mL, respectively. Samples containing aprepitant in concentrations greater than 2000 ng/mL were diluted by adding 50 µL of the plasma sample to 50 µL of phosphate-buffered saline. The intraday and interday coefficients of variation (CV%) for the assay, respectively, at the low, middle and high concentration ranges were as follows: low: 11% and 12%, middle: 9% and 9%, high: 8% and 10%.

Potential outliers were determined by visual inspection of raw data and concentration versus time plots. Any identified outliers were re-analyzed. Other samples were randomly chosen for re- analysis so that 15% of all samples were re-analyzed. If the aprepitant concentration of a sample varied by >15% from the first analysis to the second analysis, a third analysis was performed. The average of the two non-spurious samples was used in the pharmacokinetic data analysis. When samples that were deemed to be potential outliers differed by <15% from the first to the second analysis, the average of the two concentrations was used in the pharmacokinetic analysis. In all other cases, the aprepitant concentrations determined in the first run of the assay were used for pharmacokinetic analysis.

4.3.6 Pharmacokinetic Analysis

Methods for pharmacokinetic analysis conformed to the Health Canada Guidance Document for Conduct and Analysis of Comparative Bioavailability Studies.16

Non-Compartmental Analysis (NCA)

A non-compartmental analysis (NCA) was applied (Phoenix® WinNonlin® 7.0) to determine: area under the concentration versus time curve (AUC) from time zero to 24 hours (AUC0-24h);

AUC from time zero to 48 hours (AUC0-48h); AUC from time zero to infinity (AUC0-inf); maximum concentration (Cmax); time to Cmax (Tmax); elimination rate constant (ke); and half-life

(t1/2) and lag time (if any). AUC was calculated following the linear trapezoidal rule. Percent of area measured by AUC0-48h relative to the extrapolated AUC0-inf was calculated to determine if at least 70% of the total exposure to aprepitant was captured during the sampling period. The time point when log-linear elimination begins (TLIN) and the time point of the lowest quantifiable concentration (LQCT) were also determined.16 The interval between these two time points represents the time over which the log-linear elimination phase was captured during our sampling period and was used to determine ke.

Other Approaches to Modeling

Aprepitant concentration versus time data were analyzed to determine if it followed a first order, one compartment model as has previously been established19 with a plan to determine model- calculated pharmacokinetic parameters (AUC0-inf, Cmax, Tmax, ke, t1/2) if the data were shown to fit this model. The Phoenix® WinNonlin® first order, one compartment pharmacokinetic modeling function was applied to the aprepitant concentration versus time data for all 17 study volunteers. The analysis was run with user supplied NCA-derived pharmacokinetic parameter estimates and applying the Gauss-Newton (Levenberg & Hartley) minimization method for model fitting. Goodness-of-fit was assessed by visual inspection of the model-fitted curve superimposed on the observed data and the residual (observed concentration – predicted concentration) versus predicted concentration curve for each volunteer. In the event that aprepitant was shown not to follow a first order, one compartment model, exploration of other potential pharmacokinetic models was planned.

4.3.7 Statistical Considerations

Study Endpoints

Relative bioavailability, the primary endpoint for the study, was defined as the geometric least squares mean ratio of the NCA-derived AUC0-inf for the oral suspension versus the capsule expressed as a percentage.

Bioequivalence, a secondary endpoint, was defined as per the Health Canada Guidance Document for Conduct and Analysis of Comparative Bioavailability Studies.16 That is, the two formulations were to be deemed bioequivalent if: (1) the 90% CI of the geometric least squares mean of NCA-derived AUC from time zero to the last quantifiable concentration (AUC0-48h in this study) of the aprepitant oral suspension relative to the aprepitant capsule was within 80% to

125% and (2) the relative geometric least squares mean of NCA-derived Cmax of the aprepitant oral suspension to the aprepitant capsule was within 80% and 125%.

Sample Size

Based on the two one-sided test procedure, ensuring that the entire 90% CI of the geometric mean ratio of AUC0-inf falls completely between 80% and 125%, using 80% power and α=0.05, assuming a maximum difference between test and reference products of 5%, and using an average intrasubject variability for AUC of 18.8% based on aprepitant capsule data in adolescents and adults,6, 14, 20, 21 17 evaluable study volunteers were required.

Statistical Analysis

The pharmacokinetic parameters determined using NCA were used in the determination of the primary and secondary endpoints.

The arithmetic mean, standard deviation (SD), CV% and median were calculated for the plasma aprepitant concentrations for each sampling time point and formulation. NCA-derived AUC0-48h,

AUC0-inf, percent of area measured by AUC0-48h relative to the extrapolated AUC0-inf, Cmax, Tmax,

TLIN, LQCT, ke and t1/2 were similarly described.

16 Following the Health Canada guidance document recommendations, ln-transformed AUC0-24h,

AUC0-48h, AUC0-inf, and Cmax data were analyzed using the PROC MIXED procedure in SAS 9.4.

The geometric least squares mean and associated 95% CI for AUC0-24h and Cmax were specifically calculated for the aprepitant oral suspension to allow for its comparison to historical aprepitant capsule data.

An analysis of variance (ANOVA) was applied to ln-transformed AUC0-48h, AUC0-inf, and Cmax to determine the impact of order of formulation presentation (sequence), study period, and formulation on the variability seen in the aforementioned pharmacokinetic parameters between the capsule and the suspension. Sequence, period and formulation were included as fixed effects in the model. Subject within sequence (subject(sequence)) was included in the model as a random effect allowing for the determination of interpatient CV%. Intrasubject CV% was determined from the residual error term obtained from the ANOVA. The point estimates of the relative geometric least squares mean ratios for AUC0-48h, AUC0-inf, and Cmax and their respective 90% CI were constructed by exponentiation of the differences of the least square means and their upper and lower limits at an alpha of 0.1 as obtained from the ANOVA.

Studentised residual outlier testing was conducted on the NCA-derived AUC0-48h, AUC0-inf, and

Cmax data (SAS 9.4; PROC GLM). Values greater than 3 were considered statistical outliers. If a volunteer was determined to be a statistical outlier their data were to be excluded from the final data analysis.

Post-Hoc Exploratory Analysis

A post-hoc exploratory analysis was conducted to determine if a single study volunteer could influence the bioequivalence result between the aprepitant oral suspension and capsule. Dixon’s

Q Test was applied to the ratio of AUC0-48h (suspension/capsule) to determine if any single volunteer was considered an outlier. Ln-transformed AUC0-48h, AUC0-inf, and Cmax data were re- analyzed removing study volunteers that had a ratio (suspension/capsule) of <0.5 or >1.5 for

AUC0-48h using the statistical procedures described above. Only one study volunteer was removed from the dataset each time the analysis was completed.

4.4 Results

Two lots of aprepitant 125 mg capsules (Emend®, Merck Canada Inc.; lot# 460756, 482115) were administered to study volunteers and used in the preparation of the extemporaneous aprepitant oral suspension. Five batches of the oral suspension were prepared and administered to study volunteers over the course of the study.

4.4.1 Volunteer Demographics and Adverse Events

Seventeen study volunteers (6 male and 11 female) were recruited and completed the study from September to December 2017. All volunteers completed the study. Their baseline demographic information is presented in Table 4.1.

Many study volunteers (35%) experienced at least one adverse event during the study period. All adverse events were deemed to be possibly related to aprepitant administration by the qualified investigator and classified as grade 1 CTCAE v4.03. The most frequent adverse events seen after administration of both aprepitant formulations were fatigue and headache (Table 4.2). No clinically significant changes in vital signs were observed with either formulation.

4.4.2 Pharmacokinetic Parameters

There were no missing blood draws during the study periods and all samples were analyzed for aprepitant concentrations. Actual blood collection times were used to calculate the time post- aprepitant dose. One study volunteer had a detectable aprepitant concentration before administration of the aprepitant dose (sampling time zero) at the second study period (aprepitant concentration: 15.0 ng/mL). However, given that this concentration was 0.01% of the observed maximum concentration (1600 ng/mL), the study volunteer was included in the analysis. Based on initial visual inspection of the raw data, 5% of samples were potential outliers and were re- analyzed. No study volunteer was found to be an outlier based on the studentised residual outlier testing. Thus, all samples from all study volunteers were included in the statistical analysis.

Figure 4.1 presents the average concentration versus time data for all 17 study volunteers. A lag time in absorption was not detected. The mean concentrations at 24 hours post-aprepitant administration for the capsule and suspension were 645 ng/mL (± 302 ng/mL) and 562 ng/mL (±

258 ng/mL), respectively. Arithmetic mean pharmacokinetic parameters are summarized in Table 4.3. NCA-derived pharmacokinetic parameters for individual volunteers can be found in

Tables 4.4-4.5. The geometric least squares mean and associated 95% CI for AUC0-24h and Cmax are summarized in Appendix C: Supplementary Table C1.

The NCA-derived arithmetic mean AUC0-48h was found to be 31,191 ng∙h/mL (± 12,100.6 ng∙h/mL) and 26,525 ng∙h/mL (± 8397.6 ng∙h/mL) for the capsule and oral suspension, respectively. NCA-derived arithmetic mean AUC0-inf for the capsule was found to be 36,820 ng∙h/mL (± 17,402.8 ng∙h/mL) and 29,107 ng∙h/mL (± 11,548.8 ng∙h/mL) for the suspension. All but one study volunteer had at least 70% of their AUC0-inf captured during the 48 hour sampling period. AUC0-48h/AUC0-inf for this volunteer was 75% for the aprepitant capsule and 69% for the suspension. On average, 88% (± 9.6%) of the AUC0-inf was captured within the sampling period for the aprepitant capsule and 93% (± 8.0%) for the oral suspension.

NCA-derived arithmetic mean Cmax for the capsule was found to be 1884 ng/mL (± 754.7 ng/mL) and 1593 ng /mL (± 487.5 ng /mL) for the aprepitant oral suspension. Slope plots of the individual NCA-derived AUC0-48h, AUC0-inf and Cmax values for the aprepitant capsule versus the suspension for all 17 volunteers are depicted in Figure 4.2.

4.4.3 Relative Bioavailability and Bioequivalence Determination

Relative bioavailability based on the geometric least squares mean ratio of AUC0-inf for the oral suspension versus the capsule was 82.3% (90% CI: 69.09-98.00%).

No statistically significant sequence, period or formulation effects between treatments were detected using ANOVA for ln-transformed AUC0-48h, AUC0-inf or Cmax data (Table 4.6). The intrasubject and intersubject variability seen for AUC0-48h, AUC0-inf and Cmax, were 25.53% and 28.99%, 29.64% and 36.61%, and 21.94% and 25.70%, respectively.

The geometric least squares mean ratios of the aprepitant oral suspension versus the capsule and their associated 90% CIs for AUC0-48h and Cmax were, respectively, as follows: 87.8% (90% CI: 75.48-102.16%) and 86.1% (90% CI: 75.59-98.16%) (Table 4.7). Based on these results, the bioequivalence of these two aprepitant formulations was not demonstrated.

No study volunteer was found to be an outlier based on their calculated ratio

(suspension/capsule) for AUC0-48h. Three study volunteers were found to have a ratio

(suspension/capsule) for AUC0-48h of <0.5 or >1.5. The results of the post-hoc exploratory analysis did not demonstrate that the result of bioequivalence would change by removing any one of these volunteers from the dataset (Appendix C, Section D).

4.4.4 First Order, One Compartment Model Results

Using NCA-derived pharmacokinetic parameter estimates and applying the Gauss-Newton (Levenberg & Hartley) minimization method, a first order, one compartment model was able to be fit to the concentration versus time data for all 17 study volunteers. The average pharmacokinetic parameters (AUC0-inf, Cmax, Tmax, ke, and t1/2) derived from the model are summarized in Table 4.3. The individual volunteer pharmacokinetic data can be found in Tables 4.8-4.9.

4.5 Discussion

We found the relative bioavailability of the extemporaneous aprepitant oral suspension versus the aprepitant capsule to be 82.3% (90% CI: 69.09-98.00%). Bioequivalence of these two formulations was not established. Pharmacokinetic parameters determined using NCA and the first order, one compartmental model were similar.

Based on the geometric least squares mean ratios (suspension/capsule) for AUC and Cmax, the administration of the aprepitant suspension led to lower aprepitant exposure versus the capsule. However, this was not consistently the case amongst all study volunteers (Figure 4.2). One may have expected the oral suspension to have an earlier Tmax and higher Cmax compared to the capsule since the oral suspension does not require time for disintegration of the capsule shell and solubilization of the capsule contents before the drug can be absorbed. Yet, this was not observed in our study. Observed average lower AUC and Cmax of the oral suspension may be explained by loss of drug nanoparticalization in the crushing of the aprepitant capsule contents and trituration that occurs in its preparation.

Despite not meeting bioequivalence, an argument can be made based on previously published pharmacokinetic and pharmacodynamic data to support the use of this extemporaneous

aprepitant oral suspension without dose adjustments. The pharmacokinetic parameters for the oral suspension that we observed are similar to what have been reported for healthy adult volunteers receiving the aprepitant capsule (Appendix C: Supplementary Table C1).14 Moreover, previously conducted positron emission tomography studies in healthy adult males have demonstrated that aprepitant concentrations of 100 ng/mL inhibit 90% of NK1 receptors in the 22, 23 brain. Aprepitant has been shown to have antiemetic effects when this degree of NK1 receptor inhibition is achieved.22-24 Aprepitant concentrations achieved after the administration of the suspension were well above 100 ng/mL at 24 hours post-dose in all of our study volunteers. Hence, it is reasonable to expect clinically effective antiemetic activity after administration of the extemporaneous aprepitant oral suspension.

Although the study was conducted in healthy adult volunteers, the findings are generalizable to children. First, passive and active transport processes for drug absorption in infants with normal development reach adult levels by 4 months.25 Hence, we would not expect aprepitant absorption to differ significantly in children for whom aprepitant is currently indicated – those 6 months of age and older.9 Moreover, the expected influence of CYP3A4 ontogeny on aprepitant AUC is mitigated by the recommended pediatric dose which is approximately 1.7-fold higher than the adult dose.23 That is, clinically significant differences in aprepitant exposure are not observed between children and adults when recommended doses are given. Mean aprepitant AUC0-24h with 3 mg/kg dosing using the FDA and EMA marketed 25 mg/mL aprepitant oral suspension was found to be 21,100±11,800 ng·h/mL, 17,300±5,060 ng·h/mL and 24,400±15,800 ng·h/mL in children 0.5 to <2 years, 2 to <6 years and 6 to <12 years, respectively.26, 27 A summary of the available pediatric aprepitant pharmacokinetic data are provided in Appendix C: Supplementary

Table C1. The AUC0-24h in children are similar to the AUC0-24 that was observed with the aprepitant oral suspension in this study (19,455 ng·h/mL, 95% CI: 17,795 to 21,057 ng·h/mL). The use of aprepitant with the pediatric dose of 3 mg/kg on Day 1 and 2 mg/kg on Days 2 and 3 has also been demonstrated to be safe and effective.2 Based on this knowledge, it is expected that pediatric cancer patients given this extemporaneous aprepitant oral suspension at the recommended pediatric dose will experience an antiemetic effect with no increased risk of harm.

A phenomenon regarding aprepitant pharmacokinetic disposition that has not been previously reported in humans was observed. A smaller, second aprepitant concentration peak was seen, commonly between 10-24 hours post-dose, in all of our study volunteers with one (5/17) or both 89

formulations (12/17). This may be explained by enterohepatic recirculation of aprepitant, as suggested in an early study in beagles and rats.28 However, industry-conducted pharmacokinetic studies in humans do not indicate that enterohepatic recirculation significantly contributes to the pharmacokinetic profile of aprepitant (A. Turgeon, B.Pharm., M.Sc., Merck Canada Inc., personal communication, February 16, 2018). Other potential factors that may have resulted in this second peak may be delayed gastric emptying or increased absorption of the drug in the colon. However, it is unlikely that either of these events occurred given that these were healthy volunteers with no known gastrointestinal illness and that aprepitant’s absorption is believed primarily to occur in the small intestine based on animal studies.29

The strength of this study was its adherence to the methods outlined in the Health Canada Guidance Document for Conduct and Analysis of Comparative Bioavailability Studies.16 The stringent methodology and crossover nature of the study minimized bias and controlled for factors that could potentially impact the absorption and metabolism of aprepitant. A limitation of the study lies with the compounding of the aprepitant oral suspension itself. Variability in the extent of crushing of the aprepitant capsule contents or trituration of the powder may have resulted in differences in particle size that may have, in turn, resulted in differences in aprepitant absorption. In addition, if aprepitant does undergo enterohepatic recirculation, this was not considered in the development of the study protocol. Meals at 10 to 24 hours post-aprepitant dose were not standardized which may explain some of intrapatient variability observed in this study. In addition, because the second peak was unexpected, elimination rate constants were estimated using two concentration-time points for either the oral suspension or capsule for nine of the study volunteers. Furthermore, it is also likely that this study was underpowered to demonstrate bioequivalence given that the observed intrapatient variability (29.6% for AUC0-inf and 25.5% for AUC0-48h) was higher than what was used in the original sample size calculation (18.8%). Lastly, it is important to note that the findings of this study are applicable only to the extemporaneous oral aprepitant suspension preparation evaluated in this study and not to other formulations.

To conclude, the bioavailability of the extemporaneous aprepitant oral suspension relative to the aprepitant capsule was 82.3% (90% CI: 69.09-98.00%) - sufficient to suggest therapeutic efficacy comparable to the capsule in both adults and children for the prevention of acute chemotherapy-induced vomiting. Both the aprepitant oral suspension and capsule were well- 90

tolerated by all study volunteers. Thus, the extemporaneously prepared aprepitant oral suspension used in this study is a viable option for both cancer patients unable to swallow capsules in jurisdictions where the commercial aprepitant suspension is not available.

4.6 Acknowledgments

We acknowledge the generous financial support provided by the Garron Family Cancer Centre’s Small Grant Competition and the Pediatric Oncology Group of Ontario Research Unit. Dr. Priya Patel was supported by the Pediatric Oncology Group of Ontario Research Unit Fellowship - Clinician Scholar Award. We would also like to thank the nurses and staff at the SickKids’ Clinical Research Centre for providing their clinical expertise and resources in helping to conduct the study. In addition, we could like to thank SickKids’ Research Support Pharmacy for helping to randomize our study volunteers and for preparing and dispensing the aprepitant doses. We would also like to thank the SickKids Department of Pediatric Laboratory Medicine for processing and storing the blood samples, and Hayley Craig-Barnes and Nick Stesco at the Analytical Facility for Bioactive Molecules for development and validation of the aprepitant assay, and for analyzing the study samples. Finally, we would like to thank Dr. Micheline Piquette-Miller and Dr. Beth Sproule and members of the SickKids’ Department of Pharmacy for their support and guidance on the project.

Table 4.1 Baseline demographics of study volunteers Characteristic Mean ± SD Median Range Age (years) 27.4 ± 7.7 25.1 21.2-54.8 Height (cm) 165.7 ± 8.7 165.0 151.1-178.1 Weight (kg) 65.1 ± 10.7 62.3 48.6-81.2 BMI (kg/m2) 23.6 ± 2.8 23.2 18.5-29.6

Table 4.2 Summary of adverse events Number of Patients (%) Adverse Event Capsule Suspension Overall Total 5 (29) 5 (29) 6 (35) Fatigue 2 (12) 3 (18) 4 (24)a Headache 3 (18) 1 (6) 3 (18)a Hiccups 0 (0) 1 (6) 1 (6) aOne study volunteer experienced the adverse event with both aprepitant formulations

Table 4.3 Arithmetic mean pharmacokinetic parameters for aprepitant from noncompartmental analysis and first order, one compartment model analysis First order, one compartment Pharmacokinetic Noncompartmental Analysis model Parameter Capsule Suspension Capsule Suspension AUC0-48h (ng∙h/mL) ± SD 31191± 12100.6 26525 ± 8397.6 N/A N/A AUC0-inf (ng∙h/mL) ± SD 33295.5 ± 26623.4 ± 36820 ± 17402.8 29107 ± 11548.8 22173.59 11686.31 AUC0-48h/AUC0-inf (%) ± 88 ± 9.6 94 ± 8.0 N/A N/A SD Cmax (ng/mL) ± SD 1884 ± 754.7 1593 ± 487.5 1371 ± 560.4 1176± 320.9 Tmax (h) ± SD 3.5 ± 1.84 4.2 ± 2.31 3.8 ± 1.42 4.6 ± 2.01 TLIN(h) ± SD 27.3 ± 3.95 25.8 ± 3.36 N/A N/A LQCT(h) ± SD 48.0 ± 0.25 48.1 ± 0.21 N/A N/A -1 ke (h ) 0.063 ± 0.034 0.078 ± 0.027 0.096 ± 0.096 0.086 ± 0.069 t1/2(h) ± SD 13.8 ± 6.67 10.4 ± 5.31 14.6 ± 11.29 12.0 ± 6.41 Cmax, maximum concentration; Tmax, time to Cmax; AUC0-48h, area under the concentration versus time curve from time zero to 48 hours; AUC0-inf, area under the concentration versus time curve from time zero to infinity; TLIN, time point for where log-linear elimination begins; LQCT, lowest quantifiable concentration time; ke, elimination rate constant; t1/2, half-life; SD, standard deviation; N/A, not applicable

Table 4.4 Noncompartmental analysis-derived parameter estimates for each subject given an aprepitant 125 mg capsule

AUC0-48h/ ke Cmax Tmax LQCT AUC0-t AUC0-inf TLIN - t1/2 Study ID AUC0-inf (hours (ng/mL) (hours) (hours) (ng∙h/mL) (ng∙h/mL) (hours) (hours) (%) 1) APREP1 1800 4.0 48.0 17560 18157 96.7 24 0.076 9.2 APREP2 1360 3.0 47.3 19413 19565 99.2 31.9 0.158 4.4 APREP3 1870 3.0 48.1 25914 26924 96.3 24.1 0.070 9.9 APREP4 1600 3.1 47.8 46503 63920 72.8 32.0 0.036 19.3 APREP5 1410 4.0 47.7 24091 24716 97.5 31.7 0.093 7.5 APREP6 1860 3.0 47.9 38151 44101 86.5 31.7 0.052 13.2 APREP7 1310 3.0 47.9 21826 27913 78.2 32.2 0.032 21.9 APREP8 2940 4.0 47.8 49263 57826 85.2 31.7 0.059 11.7 APREP9 942 10.0 48.2 19296 20478 94.2 23.8 0.065 10.6 APREP10 1540 4.0 48.5 30411 34798 87.4 24.2 0.047 14.6 APREP11 2360 2.0 48.2 37011 38952 95.0 31.7 0.064 10.8 APREP12 1670 3.0 47.9 36939 45600 81.0 24.2 0.038 18.1 APREP13 4160 2.0 48.2 52875 75199 70.3 24.1 0.022 30.8 APREP14 2000 3.7 48.1 44379 49031 90.5 24.0 0.056 12.4 APREP15 1290 3.0 48.0 12469 12537 99.5 24.1 0.118 5.9 APREP16 2310 2.0 48.0 25454 27858 91.4 24.1 0.054 12.9 APREP17 1610 2.0 48.0 28687 38360 74.8 24.2 0.033 21.0

Mean 1884.2 3.5 48.0 31191 36820 88.0 27.3 0.063 13.8 SD 754.71 1.84 0.25 12100.6 17402.8 9.59 3.95 0.034 6.67 CV (%) 40.05 53.11 0.51 38.8 47.3 10.90 14.47 53.87 48.40 Median 1670.0 3.0 48.0 28687 34798 90.5 24.2 0.056 12.4 SD, standard deviation; CV, coefficient of variation; LQCT, last quantifiable concentration; Cmax, maximum concentration; Tmax, time to Cmax; AUC0-t, area under the concentration time curve from time 0 to LCQT; AUC0-inf, area under the concentration vs time curve from time 0 to infinity; TLIN, time point where log-linear elimination begins; ke, elimination rate constant; t1/2, ha

Table 4.5 Noncompartmental analysis-derived parameter estimates for each subject given aprepitant 125 mg as the extemporaneous oral suspension

AUC0-48h/ ke Cmax Tmax LQCT AUC0-t AUC0-inf TLIN - t1/2 Study ID AUC0-inf (hours (ng/mL) (hours) (hours) (ng∙h/mL) (ng∙h/mL) (hours) (hours) (%) 1) APREP1 1850 4.0 48.1 31601 32149 98.3 32.0 0.092 7.5 APREP2 846 4.0 48.3 14347 14425 99.5 24.4 0.120 5.8 APREP3 1090 4.03 48.1 15830 15938 99.3 31.9 0.124 5.6 APREP4 1320 4.0 48.0 32974. 40949 80.5 31.8 0.041 16.9 APREP5 1230 4.03 48.1 21183 22085 95.9 31.0 0.071 9.7 APREP6 1190 9.9 47.8 28565 30080 95.0 23.8 0.075 9.2 APREP7 1930 3.0 48.0 24146 27300 88.5 24.0 0.045 15.4 APREP8 2500 3.0 48.1 38485 40890 94.1 23.7 0.058 11.9 APREP9 880 2.1 48.5 16675 17159 97.2 24.3 0.083 8.4 APREP10 2220 3.0 47.9 31782 33288 95.5 23.7 0.076 9.2 APREP11 1530 2.0 47.8 26540 27214 97.5 24.0 0.087 7.9 APREP12 1290 10.0 47.9 31829 33717 94.4 24.4 0.072 9.6 APREP13 2260 4.0 48.2 26202 27161 96.5 23.9 0.073 9.6 APREP14 1580 4.0 47.9 19279 19559 98.6 24.0 0.104 6.7 APREP15 1600 4.0 48.6 14973 15106 99.1 24.1 0.111 6.2 APREP16 1800 4.0 48.1 37109 40438 91.8 24.1 0.060 11.5 APREP17 1960 2.0 48.1 39410 57368 68.7 24.0 0.026 26.3

Mean 1592.7 4.2 48.1 26525 29107 93.5 25.8 0.078 10.4 SD 487.46 2.31 0.21 8397.6 11548.8 7.96 3.36 0.027 5.1 CV (%) 30.61 55.26 0.45 31.7 39.7 8.51 13.03 35.12 49.2 Median 1580.0 4.0 48.1 26540 27300 95.9 24.1 0.075 9.2 SD, standard deviation; CV, coefficient of variation; LQCT, last quantifiable concentration; Cmax, maximum concentration; Tmax, time to Cmax; AUC0-t, area under the concentration time curve from time 0 to LCQT; AUC0-inf, area under the concentration vs time curve from time 0 to infinity; TLIN, time point where log-linear elimination begins; ; ke, elimination rate constant; t1/2, half- life

Table 4.6 Summary of p -values for treatment, period and sequence effects for the pharmacokinetic parameters of aprepitant Pharmacokinetic p-valuesa Parameter Sequence Period Treatment AUC0-48h 0.6945 0.1083 0.1530 AUC0-inf 0.9027 0.1070 0.0694 Cmax 0.3292 0.3088 0.0637 AUC0-48h, area under the concentration versus time curve from time zero to 48 hours; AUC0-inf, area under the concentration versus time curve from time zero to infinity; Cmax, maximum concentration ap-value<0.05 represents a significant effect

Table 4.7 Geometric least mean squares ratio, 90% confidence intervals and variance estimates of pharmacokinetic parameters for aprepitant 20 mg/mL oral suspension versus 125 mg oral capsule Geo-LS 90% Subject Pharmacokinetic Geo-LS Residual Intrasubject Intersubject Formulation mean confidence (sequence) Parameter mean varianceb variability variability ratioa interval varianceb AUC0-48h 25341 75.48- Suspension 87.8% 0.08072 0.06316 25.5% 29.0% ng∙h/mL 102.16% 28858 Capsule ng∙h/mL AUC0-inf 27318 69.09- Suspension 82.3% 0.1258 0.08419 29.6% 36.6% ng∙h/mL 98.00% 33198 Capsule ng∙h/mL Cmax 1530 75.59- Suspension 86.1% 0.06395 0.04702 21.9% 25.7% ng/mL 98.16% 1776 Capsule ng/mL Geo-LS, geometric least square; AUC0-48h, area under the concentration versus time curve from time zero to 48 hours; AUC0-inf, area under the concentration versus time curve from time zero to infinity; Cmax, maximum concentration aRatio is of the geometric least squares mean of the pharmacokinetic parameter for the aprepitant oral suspension/oral capsule*100% bVariance as obtained from the ANOVA of ln-transformed pharmacokinetic parameter

Table 4.8 First order, one compartment model-derived parameter estimates for each subject given aprepitant capsule

AUC0-inf -1 Study ID Cmax (ng/mL) Tmax (hours) ke (hours ) t1/2 (hours) (ng∙h/mL) APREP1 1095 4.1 12327 0.240 2.9 APREP2 1032 2.9 15674 0.084 8.3 APREP3 1360 3.9 23238 0.080 8.6 APREP4 1246 6.2 96122 0.014 49.0 APREP5 1080 2.9 24521 0.051 13.5 APREP6 1205 5.2 52047 0.027 26.1 APREP7 998 2.3 18714 0.062 11.3 APREP8 1873 3.8 57802 0.037 18.5 APREP9 674 7.0 20371 0.045 15.2 APREP10 1181 4.4 34546 0.041 16.9 APREP11 1579 2.8 34505 0.053 13.0 APREP12 1280 4.0 47813 0.030 22.9 APREP13 3242 2.1 27290 0.168 4.1 APREP14 1657 5.3 52000 0.039 17.7 APREP15 1061 2.8 8175 0.352 2.0 APREP16 1552 2.9 13438 0.213 3.2 APREP17 1193 2.4 27441 0.049 14.2

Mean 1371 3.8 33296 0.096 14.6 SD 560.4 1.42 22173.6 0.096 11.29 CV (%) 40.9 36.93 66.6 100.05 77.54 Median 1205 3.8 27290 0.052 13.5 SD, standard deviation; CV, coefficient of variation; Cmax, maximum concentration; Tmax, time to Cmax; AUC0-inf, area under the concentration vs time curve from time 0 to infinity; ke, elimination rate constant; t1/2, half-life

Table 4.9 First order, one compartment model-derived parameter estimates for each subject given aprepitant suspension

AUC0-inf -1 Study ID Cmax (ng/mL) Tmax (hours) ke (hours ) t1/2 (hours) (ng∙h/mL) APREP1 1354 3.9 33501 0.049 14.2 APREP2 735 7.1 14130 0.143 4.8 APREP3 749 5.0 16371 0.062 11.1 APREP4 1059 5.6 45948 0.027 25.9 APREP5 894 4.5 23256 0.048 14.6 APREP6 1056 10.5 30055 0.091 7.6 APREP7 1305 3.5 17811 0.105 6.6 APREP8 1803 3.2 34396 0.064 10.8 APREP9 676 4.1 16722 0.050 14.0 APREP10 1467 3.2 29884 0.059 11.7 APREP11 1203 3.2 25830 0.056 12.4 APREP12 1031 7.1 37053 0.036 19.3 APREP13 1639 3.1 16411 0.169 4.1 APREP14 1112 3.3 13915 0.118 5.9 APREP15 1088 3.4 10034 0.303 2.3 APREP16 1286 4.4 42273 0.036 19.5 APREP17 1531 2.7 45009 0.038 18.4

Mean 1176 4.6 26623 0.086 12.0 SD 320.9 2.01 11686.3 0.068 6.41 CV (%) 27.3 43.98 43.9 78.33 53.62 Median 1112 3.9 25830 0.059 11.7 SD, standard deviation; CV, coefficient of variation; Cmax, maximum concentration; Tmax, time to Cmax; AUC0-inf, area under the concentration vs time curve from time 0 to infinity; ke, elimination rate constant; t1/2, half-life

Figure 4.1 Average aprepitant concentration versus time profile for all 17 study volunteers for the oral aprepitant capsule and oral suspension

2500

2000

1500

Capsule 1000 Suspension

AprepitantConcentration (ng/mL) 500

0 0 10 20 30 40 50 Time (hours)

ion

sus the oral suspension oral the sus

with the aprepitant capsule versus the oral suspension oral the capsule versus aprepitant the with

with the aprepitant capsule suspens oral the aprepitant versus the with

48h

inf -

with the aprepitant capsule ver aprepitant the with

max

Slope plot comparing study volunteers’ AUC Slopecomparing plot

Slope plot comparing study volunteers’ C study volunteers’ Slopecomparing plot

Slope plot comparing study volunteers’ AUC volunteers’ study Slopecomparing plot a

Figure 4.2 Figure a b c

4.7 References

1. American Society of Clinical O, Kris MG, Hesketh PJ, Somerfield MR, Feyer P, Clark- Snow R, et al. American Society of Clinical Oncology guideline for antiemetics in oncology: update 2006. J Clin Oncol. 2006;24(18):2932-47.

2. Kang HJ, Loftus S, Taylor A, DiCristina C, Green S, Zwaan CM. Aprepitant for the prevention of chemotherapy-induced nausea and vomiting in children: a randomised, double- blind, phase 3 trial. Lancet Oncol. 2015;16(4):385-94.

3. Bakhshi S, Batra A, Biswas B, Dhawan D, Paul R, Sreenivas V. Aprepitant as an add-on therapy in children receiving highly emetogenic chemotherapy: a randomized, double-blind, placebo-controlled trial. Support Care Cancer. 2015;23(11):3229-37.

4. Bauters TG, Verlooy J, Robays H, Benoit Y, Laureys G. Emesis control by aprepitant in children and adolescents with chemotherapy. Int J Clin Pharm. 2013;35(6):1021-4.

5. Bodge M, Shillingburg A, Paul S, Biondo L. Safety and efficacy of aprepitant for chemotherapy-induced nausea and vomiting in pediatric patients: a prospective, observational study. Pediatr Blood Cancer. 2014;61(6):1111-3.

6. Gore L, Chawla S, Petrilli A, Hemenway M, Schissel D, Chua V, et al. Aprepitant in adolescent patients for prevention of chemotherapy-induced nausea and vomiting: a randomized, double-blind, placebo-controlled study of efficacy and tolerability. Pediatr Blood Cancer. 2009;52(2):242-7.

7. Dupuis LL, Sung L, Molassiotis A, Orsey AD, Tissing W, van de Wetering M. 2016 updated MASCC/ESMO consensus recommendations: Prevention of acute chemotherapy- induced nausea and vomiting in children. Support Care Cancer. 2017;25(1):323-31.

8. Hesketh PJ, Kris MG, Basch E, Bohlke K, Barbour SY, Clark-Snow RA, et al. Antiemetics: American Society of Clinical Oncology Clinical Practice Guideline Update. J Clin Oncol. 2017;35(28):3240-61.

9. Patel P, Robinson PD, Thackray J, Flank J, Holdsworth MT, Gibson P, et al. Guideline for the prevention of acute chemotherapy-induced nausea and vomiting in pediatric cancer patients: A focused update. Pediatr Blood Cancer. 2017;64(10).

10. Merck & Co., Inc. Emend (aprepitant) Product Monograph [Internet]. Merck Sharp & Dohme Corp.; 2017 May [cited 2018 January 8]. Available from: http://www.merck.com/product/usa/pi_circulars/e/emend/emend_pi.pdf.

11. European Medicines Agency. Emend (aprepitant) product information (Internet). London: European Medicines Agency; 2017 November 10 [cited 2018 January 8]. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_- _Product_Information/human/000527/WC500026537.pdf.

12. Dupuis LL, Lingertat-Walsh K, Walker SE. Stability of an extemporaneous oral liquid aprepitant formulation. Support Care Cancer. 2009;17(6):701-6. 99

13. European Medicines Agency. Emend (aprepitant) scientific discussion [Internet]. London: European Medicines Agency; 2006 September 5 [cited 2018 January 8]. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_- _Scientific_Discussion/human/000527/WC500026534.pdf.

14. Majumdar AK, Howard L, Goldberg MR, Hickey L, Constanzer M, Rothenberg PL, et al. Pharmacokinetics of aprepitant after single and multiple oral doses in healthy volunteers. J Clin Pharmacol. 2006;46(3):291-300.

15. Health Canada Drug Product Database. Emend (aprepitant) Product Monograph [Internet]. Kirkland (QC): Merck Canada Inc.; 2014 January 22 [cited 2018 January 8]. Available from: https://pdf.hres.ca/dpd_pm/00023565.pdf.

16. Health Canada. Guidance for Industry - Conduct and Analysis of Comparative Bioavailability Studies [Internet]. Ottawa: Health Canada; 2012 May [cited 2018 January 8]. Available from: https://www.canada.ca/content/dam/hc-sc/migration/hc-sc/dhp- mps/alt_formats/pdf/prodpharma/applic-demande/guide-ld/bio/gd_cbs_ebc_ld-eng.pdf.

17. US Department of Health and Human Services. National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03, 2010. 2016.

18. Wu D, Paul DJ, Zhao X, Douglas SD, Barrett JS. A sensitive and rapid liquid chromatography-tandem mass spectrometry method for the quantification of the novel neurokinin-1 receptor antagonist aprepitant in rhesus macaque plasma, and cerebral spinal fluid, and human plasma with application in translational NeuroAIDs research. J Pharm Biomed Anal. 2009;49(3):739-45.

19. Nakade S, Ohno T, Kitagawa J, Hashimoto Y, Katayama M, Awata H, et al. Population pharmacokinetics of aprepitant and dexamethasone in the prevention of chemotherapy-induced nausea and vomiting. Cancer Chemother Pharmacol. 2008;63(1):75-83.

20. Shadle CR, Murphy MG, Liu Y, Ho M, Tatosian D, Li S, et al. A Single-Dose Bioequivalence and Food Effect Study With Aprepitant and Fosaprepitant Dimeglumine in Healthy Young Adult Subjects. Clin Pharm Drug Dev. 2012;1(3):93-101.

21. Takahashi T, Nakamura Y, Tsuya A, Murakami H, Endo M, Yamamoto N. Pharmacokinetics of aprepitant and dexamethasone after administration of chemotherapeutic agents and effects of plasma substance P concentration on chemotherapy-induced nausea and vomiting in Japanese cancer patients. Cancer Chemoth Pharm. 2011;68(3):653-9.

22. U.S. Food and Drug Administration. Drug Approval Package Emend (Aprepitant) [Internet]. Silver Spring (MD): U.S. Food and Drug Administration; 2003 March [cited 2018 March 1]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2003/21- 549_Emend.cfm.

23. European Medicines Agency. Emend (aprepitant) assessment report [Internet]. London: European Medicines Agency; 2015 October 22 [cited 2018 January 8]. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Assessment_Report_- _Variation/human/000527/WC500200826.pdf. 100

24. Chawla SP, Grunberg SM, Gralla RJ, Hesketh PJ, Rittenberg C, Elmer ME, et al. Establishing the dose of the oral NK1 antagonist aprepitant for the prevention of chemotherapy- induced nausea and vomiting. Cancer. 2003;97(9):2290-300.

25. Kearns GL, Abdel-Rahman SM, Alander SW, Blowey DL, Leeder JS, Kauffman RE. Developmental pharmacology--drug disposition, action, and therapy in infants and children. N Engl J Med. 2003;349(12):1157-67.

28. Huskey SE, Dean BJ, Doss GA, Wang Z, Hop CE, Anari R, et al. The metabolic disposition of aprepitant, a substance P receptor antagonist, in rats and dogs. Drug Metab Dispos. 2004;32(2):246-58.

29. Wu Y, Loper A, Landis E, Hettrick L, Novak L, Lynn K, et al. The role of biopharmaceutics in the development of a clinical nanoparticle formulation of MK-0869: a Beagle dog model predicts improved bioavailability and diminished food effect on absorption in human. Int J Pharm. 2004;285(1-2):135-46.

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Chapter 5 Discussion and Conclusions

« Heading styles 1-9 is body: Heading 1 » 5.1 Summary of Key Findings

Currently published observational and RCTs support the use of aprepitant in combination with a

1-9 5-HT3 receptor antagonist and dexamethasone for the prevention of acute CINV in children. Given the significant reduction in CINV control rates that are achieved with the addition of aprepitant to a child’s antiemetic regimen and its good safety profile, this triple regimen is currently the best antiemetic option for children receiving HEC not known or suspected to interact with aprepitant. This is reflected in the updated POGO clinical practice guideline recommendations for the prevention of acute CINV in children.10 However, there are two barriers to the use of this effective medication in children: known and potential aprepitant-drug interactions and lack of a commercially available aprepitant oral liquid formulation in some jurisdictions. The systematic review of aprepitant-drug interactions aimed to clarify which drugs aprepitant is safe to administer with and those where concomitant administration of aprepitant should be avoided.11 The relative bioavailability study aimed to describe the absorption of an extemporaneous aprepitant oral suspension relative to the commercially available capsule, such that healthcare providers could prescribe it with confidence and patients unable to swallow capsules could use this effective medication.

The results of the systematic review of aprepitant and fosaprepitant drug-drug interactions indicated that there are victim drugs, both antineoplastic and non-antineoplastic, whose pharmacokinetic parameters of exposure, AUC and Cmax, would be significantly altered in the presence of aprepitant (i.e. bosutinib, cabazitaxel, cyclophosphamide, dexamethasone, methylprednisolone, midazolam, oxycodone and tolbutamide).11 However, there were interactions that were suspected to occur, given the victim drug’s metabolism through CYP3A4, which did not result in a significant change in AUC and Cmax when aprepitant was administered concomitantly (i.e. dinaciclib, docetaxel, vinorelbine, dolasetron, ondansetron, granisetron, and palonosetron).11 Considering whether a drug has routes of metabolism and elimination other than CYP3A4-mediated pathways is important to determining if an interaction with aprepitant is

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likely to be significant or not. Aprepitant’s potential to increase exposure to an antineoplastic agent may lead to late dose-related toxicities such as cardiotoxicity, nephrotoxicity, hepatotoxicity and pulmonary toxicities.12 The influence of age, disease state, genotype (if known), and concurrent drug therapy on CYP3A4 activity should also be considered when determining the clinical importance of an interaction. Since many antineoplastic agents used commonly in both adults and children have not actually been studied, antineoplastic agents that have not been evaluated for a drug interaction with aprepitant and are metabolized by CYP3A4 are still best avoided. The information provided by this systematic review improves clarity and helps guide practitioners regarding the safety of drugs co-administered with aprepitant.

The randomized, two-period, crossover relative bioavailability study supports the prescribing of the extemporaneous oral aprepitant suspension for patients, particularly children, who are unable to swallow capsules. The bioavailability of the aprepitant oral suspension was sufficient to produce an antiemetic effect although bioequivalence with the aprepitant capsule was not established. The available pediatric pharmacokinetic data furthermore suggests that the impact of pediatric development on the absorption and metabolism of aprepitant, when administered at the currently recommended pediatric dose, are not significant enough to result in clinically significant differences in aprepitant exposure compared to adults.13, 14 Hence, the results of this study are thought to be generalizable to children.

5.2 Strengths and Limitations

The strength of all of the papers included in this thesis is the rigorous methodological approach taken in conducting these projects. The clinical practice guideline followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting system15 as well as used the GRADE approach to developing recommendations.16, 17 The systematic review of aprepitant drug interactions also used the PRISMA approach. The crossover study followed the Health Canada Guidance Document for Conduct and Analysis of Comparative Bioavailability Studies.18 These are well-established methodologies for conducting the respective types of studies.

The update of the clinical practice guideline was limited by the available pediatric literature.10 First, there were differences in definitions used to define acute CINV. While some authors used

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the guideline definition of acute CINV (i.e. CINV on each day of chemotherapy plus in the 24 hours following), some authors only reported CINV control rates for the first 24 hours of a multi- day chemotherapy block. Hence, it was difficult to ascertain the effectiveness of aprepitant for patients receiving multi-day chemotherapy. Another limitation of the available evidence was that there were no data describing the use of aprepitant in children less than 6 months of age. Hence, a recommendation for its use in this population could not be made.

The primary limitation of the systematic review of aprepitant-drug interactions is perhaps the direct lack of evidence in the pediatric population. The systematic review of aprepitant-drug interactions did not identify a single study that was conducted in children.11 Similarly, the relative bioavailability study of the extemporaneous oral suspension of aprepitant was performed in adults, not children. The relative bioavailability study was initially intended to be conducted in children; however, due to challenges with recruitment, the study was not deemed to be feasible and closed. It should also be noted that the results of the relative bioavailability study are only applicable to the extemporaneous formulation of aprepitant that was studied and cannot be translated to other formulations. Nevertheless, the results of these studies will guide practitioners in their decision making with respect to the safe and effective use of aprepitant.

5.3 Future Research

Future research should focus on continued prospective evaluation of the efficacy and safety of aprepitant in children.

As previously mentioned, current evidence to support the use of aprepitant is limited to children 6 months and older.10 As well, aprepitant’s effectiveness for preventing CINV in patients receiving multi-day chemotherapy has not been fully explored. Studies evaluating aprepitant use in patients aged less than 6 months and patients receiving multi-day chemotherapy are important to determining the full scope of aprepitant’s effectiveness for CINV prevention in children.

Aprepitant’s effects on the immune system are also an area that needs further investigation. Prospective studies with longer durations of follow-up are needed to assess the impact of aprepitant on infection rates and the duration of neutropenia in pediatric cancer patients.

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Moreover, the significance of aprepitant interactions with antineoplastic agents commonly used in pediatric oncology and the effect of age on the extent of the interaction needs to be evaluated. Conducting aprepitant drug interaction studies in children will allow for more robust data on the clinical impact that aprepitant may have on a child’s exposure to interacting antineoplastic agents. Specifically, the impact of the potential change in exposure to an antineoplastic agent in the presence of aprepitant on the late effects of chemotherapy seen in survivors of childhood cancer needs to be evaluated.

The effectiveness of the extemporaneous oral suspension should also be assessed to confirm that there is adequate absorption of aprepitant to produce an antiemetic effect.

Investigations in the aforementioned areas will allow for the current evidence gaps with respect to the use of aprepitant in children to be filled and help practitioners make fully informed decisions about using aprepitant for CINV prevention for their patients.

5.4 Conclusions

The current evidence strongly supports the use of aprepitant in children aged 6 months and older, not receiving antineoplastic agents known or suspected to interact with aprepitant and receiving HEC. Hence, clinical practice guidelines for the prevention of acute CINV were updated to support the use of aprepitant in children.10 Barriers to the implementation of this recommendation are known and suspected aprepitant-drug interactions and the lack of a commercially available aprepitant formulation for patients unable to swallow capsules.

Results of the systematic review of aprepitant-drug interactions identified that aprepitant co- administration is best avoided with antineoplastic drugs such as, bosutinib, cabazitaxel, and cyclophosphamide.11 Considerations of whether a drug has alternate routes of metabolism and the impact of disease or ontogeny on a patient’s CYP3A4 activity are important when evaluating the significance of a potential aprepitant-drug interaction. The extemporaneous aprepitant oral suspension, while not shown to be bioequivalent to the capsule, is well-absorbed and results in sufficient aprepitant exposure to prevent CIV. This work demonstrates the potential utility for administering this extemporaneous aprepitant oral suspension in adult and pediatric cancer patients in jurisdictions where an aprepitant oral liquid is not commercially available.

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Overall, the research projects included in this thesis will guide practitioners in their selection of CINV prophylaxis for oncology patients. Our findings overcome the barriers to aprepitant use by clarifying which drugs it is safe to administer aprepitant with and by providing support for the use of an extemporaneous aprepitant oral suspension that can be administered to patients unable to swallow capsules in jurisdictions where an oral liquid formulation is unavailable.

5.5 References

1. Gore L, Chawla S, Petrilli A, Hemenway M, Schissel D, Chua V, et al. Aprepitant in adolescent patients for prevention of chemotherapy-induced nausea and vomiting: a randomized, double-blind, placebo-controlled study of efficacy and tolerability. Pediatr Blood Cancer. 2009;52(2):242-7.

2. Choi MR, Jiles C, Seibel NL. Aprepitant use in children, adolescents, and young adults for the control of chemotherapy-induced nausea and vomiting (CINV). J Pediatr Hematol Oncol. 2010;32(7):e268-71.

3. Bauters TG, Verlooy J, Robays H, Benoit Y, Laureys G. Emesis control by aprepitant in children and adolescents with chemotherapy. Int J Clin Pharm. 2013;35(6):1021-4.

4. Bodge M, Shillingburg A, Paul S, Biondo L. Safety and efficacy of aprepitant for chemotherapy-induced nausea and vomiting in pediatric patients: a prospective, observational study. Pediatr Blood Cancer. 2014;61(6):1111-3.

5. Duggin K, Tickle K, Norman G, Yang J, Wang C, Cross SJ, et al. Aprepitant reduces chemotherapy-induced vomiting in children and young adults with brain tumors. J Pediatr Oncol Nurs. 2014;31(5):277-83.

6. Shillingburg A, Biondo L. Aprepitant and fosaprepitant use in children and adolescents at an academic medical center. J Pediatr Pharmacol Ther. 2014;19(2):127-31.

7. Bakhshi S, Batra A, Biswas B, Dhawan D, Paul R, Sreenivas V. Aprepitant as an add-on therapy in children receiving highly emetogenic chemotherapy: a randomized, double-blind, placebo-controlled trial. Support Care Cancer. 2015;23(11):3229-37.

8. Kang HJ, Loftus S, Taylor A, DiCristina C, Green S, Zwaan CM. Aprepitant for the prevention of chemotherapy-induced nausea and vomiting in children: a randomised, double- blind, phase 3 trial. Lancet Oncol. 2015;16(4):385-94.

9. Felix-Ukwu F, Reichert K, Bernhardt MB, Schafer ES, Berger A. Evaluation of aprepitant for acute chemotherapy-induced nausea and vomiting in children and adolescents with acute lymphoblastic leukemia receiving high-dose methotrexate. Pediatr Blood Cancer. 2018;65(2).

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10. Patel P, Robinson PD, Thackray J, Flank J, Holdsworth MT, Gibson P, et al. Guideline for the prevention of acute chemotherapy-induced nausea and vomiting in pediatric cancer patients: A focused update. Pediatr Blood Cancer. 2017;64(10).

11. Patel P, Leeder JS, Piquette-Miller M, Dupuis LL. Aprepitant and fosaprepitant drug interactions: a systematic review. Br J Clin Pharmacol. 2017;83(10):2148-62.

12. Children's Oncology Group [Internet]. Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent and Young Adult Cancer. 2013 October [cited 2018 March 12]. Available from: http://www.survivorshipguidelines.org/pdf/LTFUGuidelines_40.pdf.

13. U.S. Food and Drug Administration. Clinical Pharmacology Review [Internet]. Silver Spring (MD): U.S. Food and Drug Administration; 2016 January [cited 1 March 2018]. Available from: https://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/DevelopmentResources/U CM467340.pdf

14. European Medicines Agency. Emend (aprepitant) assessment report [Internet]. London: European Medicines Agency; 2015 October 22 [cited 2018 January 8]. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Assessment_Report_- _Variation/human/000527/WC500200826.pdf.

15. Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gotzsche PC, Ioannidis JP, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. PLoS Med. 2009;6(7):e1000100.

16. Guyatt GH, Oxman AD, Kunz R, Falck-Ytter Y, Vist GE, Liberati A, et al. Going from evidence to recommendations. BMJ. 2008;336(7652):1049-51.

17. Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck-Ytter Y, Alonso-Coello P, et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ. 2008;336(7650):924-6.

18. Health Canada. Guidance for Industry - Conduct and Analysis of Comparative Bioavailability Studies [Internet]. Ottawa: Health Canada; 2012 May [cited 2018 January 8]. Available from: https://www.canada.ca/content/dam/hc-sc/migration/hc-sc/dhp- mps/alt_formats/pdf/prodpharma/applic-demande/guide-ld/bio/gd_cbs_ebc_ld-eng.pdf.

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Appendices Appendix A. Supplemental Material for Chapter 2: Guideline for the Prevention of Acute Chemotherapy-Induced Nausea and Vomiting in Pediatric Cancer Patients: A Focused Update

A. Guideline Panel Members

Panel Members

Panel Member Role Institution and Country

Lee Dupuis Pediatric Oncology The Hospital for Sick Children, Canada (chair) Pharmacist

Jacqueline Pediatric Pharmacist The Hospital for Sick Children, Canada Flank

Jason Pediatric Oncologist The Children's Hospital of Philadelphia, USA Freedman

Children’s Hospital, London Health Sciences Paul Gibson Pediatric Oncologist Centre, Canada

Mark Pediatric Oncology University of New Mexico, USA Holdsworth Pharmacist

Jennifer Pediatric Nurse Children’s Hospital Colorado, USA Madden Practitioner

Andrea Orsey Pediatric Oncologist Connecticut Children’s Medical Center, USA

Priya Patel Pediatric Pharmacist The Hospital for Sick Children, Canada

Leeds Children’s Hospital, Leeds, United Bob Phillips Pediatric Oncologist Kingdom

Carol Portwine Pediatric Oncologist McMaster University, Hamilton, Canada

Paula Robinson Guideline Methodologist Pediatric Oncology Group of Ontario, Canada

Lillian Sung Pediatric Oncologist The Hospital for Sick Children, Canada

Jennifer Pediatric Oncology Memorial Sloan Kettering Cancer Center, USA Thackray Pharmacist

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Conflict of Interest

Panel Member Conflicts Declared Details

Lee Dupuis (chair) Yes 1) Principal investigator for a clinical trial involving any of the objects of study, regardless of the source of funding - Olanzapine for Prevention of Chemotherapy - induced Nausea and Vomiting in Children: A Multi- Centre Feasibility Study 2) Published an editorial regarding any of the objects of study - Dupuis LL. Chemotherapy-induced vomiting in children: some progress, more questions. Lancet Oncology. 2016; 17(3):264-5.

Jacqueline Flank None

Jason Freedman None

Paul Gibson None

Mark Holdsworth None

Jennifer Madden None

Andrea Orsey Yes 1) Own Pfizer stock

Priya Patel None

Bob Phillips None

Carol Portwine None

Paula Robinson None

Lillian Sung None

Jennifer Thackray None

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B. Systematic review of primary studies evaluating aprepitant and palonosetron for acute CINV prophylaxis in children

Search Dates and Databases: The OvidSP platform was used to search MEDLINE, Medline in Process and EMBASE for articles indexed from database inception up to June 21, 2016.

Eligibility Criteria: . Primary studies, other than case reports, reported as full papers or letters to the editor (no date restriction) or conference abstracts (published in 2013 or more recently) . Evaluated one or more of the following: aprepitant, fosaprepitant or palonosetron for acute phase CINV prophylaxis in pediatric patients . Mean or median age of study participants is ≤16 years of age or ≥ 60% of study participants are ≤18 years of age . Reports the proportion of patients experiencing complete control of nausea and/or vomiting (as defined by authors) . It was possible to determine the emetogenicity of the antineoplastic therapy administered using the POGO classification guideline or an assessment is provided by the study’s author(s) . No restriction by language

Where acute phase is defined as: . Starting with the first dose of chemotherapy administered during a chemotherapy block and as ending 24 hours after administration of the last dose of chemotherapy administered during the chemotherapy block. OR . CINV control is reported starting with the first dose of chemotherapy administered during the chemotherapy block and as ending 24 hours later regardless of the duration of the chemotherapy block. A chemotherapy block is defined as a period when chemotherapy is given on consecutive days.

Note: For the 2013 guideline, the acute phase was defined as per the first bullet point above only. For this guideline update, the acute phase could also be defined as per the second bullet point above. Since the acute phase definition differed between the 2013 guideline and this update, the decision was made to repeat the original literature search and re-screen using the new acute phase definition.

Reasons for Exclusion: 1. Not a primary study 2. Conference abstract published before 2013 3. Mean or median age of study participants is >16 years of age or < 60% of study participants are ≤18 years of age 4. Does not evaluate aprepitant, fosaprepitant or palonosetron as an intervention 5. Does not report the proportion of patients experiencing complete control of acute nausea or vomiting 6. Not possible to determine the emetogenicity of the antineoplastic therapy administered using the POGO classification guideline or an assessment provided by the study’s author(s) 7. Case report 8. Duplicate or abstract version of a fully published study 9. Not retrievable 110

Supplementary Figure A1. PRISMA flowchart for the systematic review of primary studies evaluating aprepitant and palonosetron for acute CINV prophylaxis in children

Potentially relevant references identified (n=2,374)

Duplicates removed (n=271)

Citations screened by title/abstract (n=2,103)

Citations excluded as did not meet Identified by panel eligibility criteria (n=2,036) members’ files or original guideline (n=3)

Full text references retrieved for detailed evaluation (n=70) Excluded (n=58) Not pediatric patients (n=42) Does not report proportion with complete control of acute nausea or vomiting (n=6) Emetogenicity cannot be determined (n=1) Case report (n=1) Duplicate publications (n=5) Studies included in systematic Not retrievable (n=3)

review (n=12)

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Supplementary Table A1. Search strategies: systematic review of primary studies evaluating aprepitant and palonosetron for acute CINV prophylaxis in children

MEDLINE: The search strategy for OvidSP MEDLINE (1946 to June Week 2 2015) 1 (aloxi or onicit or palonosetron or "rs 25259" or "rs 25259 197" or "rs 25259-197" or rs25259 or "rs25259 197" or "rs25259-197").mp. [****palonosetron not MeSH - No registry number results****] 2 (aprepitant or emend or "l 754030" or l754030 or "mk 0869" or "mk 869" or mk0869 or mk869 or "ono 7436" or ono7436).mp. [****aprepitant not MeSH - No registry number results****] 3 or/1-2 [***Drug terms****] 4 nausea/ or vomiting/ 5 (emesis or vomit* or retch* or nauseous or nausea*).mp. 6 4 or 5 [****general nausea terms****] 7 exp neoplasms/ or exp Antineoplastic Agents/ or (cancer* or oncol* or tumour* or tumor* or malignan* or neoplas* or sarcom* or blastoma* or neuroblastoma* or leukem* or leukaem* or carcinoma* or lymphoma* or adenocarcinoma* or hodgkin* or chemotherap*).mp. 8 medical oncology/ or stem cell transplantation/ or cord blood stem cell transplantation/ or hematopoietic stem cell transplantation/ or mesenchymal stem cell transplantation/ or peripheral blood stem cell transplantation/ or bone marrow transplantation/ or transplantation, autologous/ or ((stem or marrow) adj2 transplant*).ti,ab. [****Oncology specialty or transplant terms****] 9 ((Chemotherap* adj2 induc*) or CINV).mp. or ci.fs. or chemotherap*.mp. 10 or/7-9 [***Chemo or oncology association nausea****] 11 3 and 6 and 10 [****Base clinical set****] 12 limit 11 to ("all child (0 to 18 years)" or "young adult (19 to 24 years)") 13 (infan* or neonat* or child* or adolescen* or teen* or girl* or boy* or youth* or tot or tots or toddler* or paediatric* or "pediatric*or young adult*" or (young adj2 adult*)).mp. [***Age group Textword search terms***] 14 11 and 13 [***Paediatric textword results****] 15 12 or 14 [****Age group results****] 16 limit 11 to ("adult (19 to 44 years)" or "middle age (45 to 64 years)" or "all aged (65 and over)" or "aged (80 and over)") 17 11 not (15 or 16) [***No age group indexing****] 18 15 or 17 [****FINAL Results****] 19 remove duplicates from 18

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MEDLINE in Process: The search strategy for OvidSP MEDLINE(R) In-Process & Other Non- Indexed Citations to June 21, 2016) 1 (aloxi or onicit or palonosetron or "rs 25259" or "rs 25259 197" or "rs 25259-197" or rs25259 or "rs25259 197" or "rs25259-197").mp. [****palonosetron not MeSH - No registry number results****] 2 (aprepitant or emend or "l 754030" or l754030 or "mk 0869" or "mk 869" or mk0869 or mk869 or "ono 7436" or ono7436).mp. [****aprepitant not MeSH - No registry number results****] 3 neurokinin 1 receptor antagonist/ 4 or/1-3 5 (emesis or vomit* or retch* or nauseous or nausea* or CINV).mp. 6 (Antineoplastic* or cancer* or oncol* or tumour* or tumor* or malignan* or neoplas* or sarcom* or blastoma* or neuroblastoma* or leukem* or leukaem* or carcinoma* or lymphoma* or adenocarcinoma* or hodgkin* or chemotherap*).mp. 7 (oncology or ((autologous or stem or marrow) adj2 transplant*)).ti,ab. 8 or/6-7 9 4 and 5 and 8 10 (infan* or neonat* or child* or adolescen* or teen* or girl* or boy* or youth* or tot or tots or toddler* or paediatric* or "pediatric*or young adult*" or (young adj2 adult*)).mp. 11 9 and 10 12 (adult* or "middle age*" or aged or geriatric* or gerontolog* or older or senior* or retiree* or retired).ti,ab. 13 9 and 12 14 9 not (11 or 13) 15 11 or 14

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EMBASE: The search strategy for OvidSP Embase Classic+Embase <1947 to 2015 Week 47> 1 palonosetron/ or (aloxi or onicit or palonosetron or "rs 25259" or "rs 25259 197" or "rs 25259-197" or rs25259 or "rs25259 197" or "rs25259-197").mp. 2 (135729-61-2 or 135729-62-3).rn. 3 aprepitant/ or (aprepitant or emend or "l 754030" or l754030 or "mk 0869" or "mk 869" or mk0869 or mk869 or "ono 7436" or ono7436).mp. 4 (170729-80-3 or 221350-96-5).rn. 5 or/1-4 [***Drug terms****] 6 "nausea and vomiting"/ or nausea/ or retching/ or vomiting/ 7 (emesis or vomit* or retch* or nauseous or nausea* or CINV).mp. 8 6 or 7 [****general nausea terms****] 9 exp neoplasm/ or exp Antineoplastic Agent/ or (cancer* or oncol* or tumour* or tumor* or malignan* or neoplas* or sarcom* or blastoma* or neuroblastoma* or leukem* or leukaem* or carcinoma* or lymphoma* or adenocarcinoma* or hodgkin* or chemotherap*).mp. 10 oncologist/ or oncology/ or oncology nursing/ or oncology ward/ or stem cell transplantation/ or hematopoietic stem cell transplantation/ or allogeneic hematopoietic stem cell transplantation/ or autologous hematopoietic stem cell transplantation/ or allogeneic stem cell transplantation/ or allogeneic hematopoietic stem cell transplantation/ or allogeneic peripheral blood stem cell transplantation/ or autologous stem cell transplantation/ or autologous hematopoietic stem cell transplantation/ or autologous peripheral blood stem cell transplantation/ or cord blood stem cell transplantation/ or in utero stem cell transplantation/ or limbal stem cell transplantation/ or mesenchymal stem cell transplantation/ or neural stem cell transplantation/ or nonmyeloablative stem cell transplantation/ or peripheral blood stem cell transplantation/ or allogeneic peripheral blood stem cell transplantation/ or autologous peripheral blood stem cell transplantation/ or autotransplantation/ or bone marrow transplantation/ or allogenic bone marrow transplantation/ or autologous bone marrow transplantation/ [****Neoplasms terms****] 11 or/9-10 [***Chemo or oncology association nausea****] 12 8 and 11 [****Chemo/Oncology associated nausea****] 13 chemotherapy induced emesis/ or "chemotherapy induced nausea and vomiting"/ 14 11 or 12 [***Chemo or oncology association nausea****] 15 5 and 14 [****Base clinical set****] 16 limit 15 to (infant or child or preschool child <1 to 6 years> or school child <7 to 12 years> or adolescent <13 to 17 years>) 17 limit 15 to (adult <18 to 64 years> or aged <65+ years>) 18 (infan* or neonat* or child* or adolescen* or teen* or girl* or boy* or youth* or tot or tots or toddler* or paediatric* or "pediatric*or young adult*" or (young adj2 adult*)).mp. [***Age group Textword search terms***] 19 15 and 18 20 16 or 19 21 15 not (20 or 17) 22 remove duplicates from 21

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Supplementary Table A2. Summary of studies used to inform recommendations 1.1-1.6: highly emetogenic antineoplastic therapy as ranked by POGO Guideline for Classification of the Acute Emetogenic Potential of Antineoplastic Medication in Pediatric Cancer Patients First Author Antiemetic Agents Evaluateda Study Design Number of Response Definition and Results (Year of Publication) Patients RANDOMIZED CONTROL TRIALS APREPITANT Bakhshi (2015) 1 G1: ondansetron 0.15mg/kg IV (max: 16mg) pre- Randomized, 93 Complete control defined as: no vomiting and no retching chemo and 0.3mg/kg/dose PO q8h, dexamethasone double-blind, after the administration of the first chemotherapy dose until [study closed before 0.15 mg/kg/dose IV pre-chemo and then PO q8h + placebo controlled 24 hours after the last chemotherapy dose in the block reaching the planned aprepitant: study number of patients as - 15-40kg: 80 mg PO days 1-3; Complete control: per the protocol due - 41-65kg: 125mg PO day 1, 80 mg PO days 2 and 3 G1: 48% (24/50) to poor accrual] vs G2: 12% (5/43) G2: ondansetron 0.15mg/kg IV (max 16mg) pre- p<0.001 chemo and 0.3mg/kg/dose PO q8h , dexamethasone 0.15 mg/kg/dose IV pre-chemo and then PO q8h + placebo Long (2015) G1: ondansetron, dexamethasone + aprepitant vs Randomized, open, 15 enrolled, 13 Complete control defined as: no emesis and no use of 2[abstract] G2: ondansetron, dexamethasone + olanzapine crossover feasibility completed breakthrough medications on day 1 *with additional study study (27 information from chemo-therapy Complete control: ASPHO poster blocks) G1: 77% (10/13) G2: 79% (11/14) No p-value provided. Panel calculated p = 1 PALONOSETRON Tang (2013) 3 G1: palonosetron 0.25 mg IV once Randomized trial 80 Complete control of vomiting defined as: no emesis within [Chinese] vs 24 hours of completion of chemotherapy G2: ondansetron 16 mg IV daily for duration of chemotherapy Complete control of vomiting: G1: 70% (28/40) G2: 65% (26/40) p-value: 0.633

Complete control of nausea defined as: no nausea on day 1

Complete control of nausea: G1: 83% (33/40) G2: 75% (30/40) p-value: 0.412 aWhere dose and/or route of administration for antiemetics is/are not listed, this information was not provided by study authors. 115

Supplementary Table A3. Summary of studies used to inform recommendation 1.1-1.6: highly emetogenic antineoplastic therapy as ranked by study investigators where insufficient information available to assign emetogenic risk using the POGO Guideline for Classification of the Acute Emetogenic Potential of Antineoplastic Medication in Pediatric Cancer Patients First Author Antiemetic Agents Study Number of Patients Response Definition and Results (Year of Publication) Evaluateda Design RANDOMIZED CONTROL TRIALS APREPITANT Kang (2015) 4 G1: ondansetron + Randomized, 302 Complete control defined as: no vomiting, no retching and no use of rescue antiemetic aprepitant 3 mg/kg (max: double-blind, (200 patients agents during first 24 hours 125 mg) PO on day 1, and 2 placebo- received very highly mg/kg (max: 80 mg) PO on controlled emetogenic Complete control: days 2 and 3 ± chemotherapy; of G1: 65% (64/99) dexamethasone IV vs these, an unknown Note: 0 to 42% of these patients received G2: ondansetron + placebo ± number received dexamethasone. dexamethasone IV dexamethasone) G2: 51% (51/101) Note: 0 to 44% of these patients received dexamethasone. No p-value provided. Panel calculated p = 0.047; panel calculated 95% confidence interval of the difference between G1 and G2: 0.2% to 28% PALONOSETRON Kovacs (2016)5 G1: palonosetron 10 µg/kg Double- 493 Complete control defined as: no vomiting, no retching and no use of rescue antiemetic IV once (max: 0.75 blind, (154 Patients agents during first 24 hours mg/dose) ± corticosteroid double receiving highly vs dummy, emetogenic In children receiving HEC or MEC (n=493): G2: palonosetron 20 µg/kg phase 3, chemotherapy: Non-inferiority of palonosetron 20 µg/kg once (max: 1.5 mg/dose) vs. ondansetron 150 IV once (max: 1.5 mg/dose) non- G1: 54 µg/kg/dose (max: 10.67 mg/dose) q4h x 3 demonstrated ± corticosteroid vs inferiority G2: 49 G3: ondansetron 150 study G3: 51) Complete control (HEC): µg/kg/dose (max: 10.67 Number of patients G1: 43% (23/54) mg/dose) IV q4h x 3 ± who received G2: 51% (25/49) corticosteroid corticosteroids G3: 41% (21/51) during acute phase No p-value provided. G1 vs. G3: Panel calculated p = 1; G2 vs. G3: panel calculated p = 0.42; is unknown. panel calculated 95% confidence interval of the difference between G2 vs. G3:-14% to 33%

Subgroup results from patients receiving HEC: Complete control (no dexamethasone, 1 day chemotherapy regimen)b: G1: 61% (11/18) G2: 60% (12/20) G3: 42% (8/19) No p-value provided. G1 vs. G3: Panel calculated p = 0.25; panel calculated 95% confidence a Where dose and/or route of administration for antiemetics is/are not listed, this information116 was not provided by study authors. bData obtained from personal communication with Kovacs (2016)

First Author Antiemetic Agents Study Number of Patients Response Definition and Results (Year of Publication) Evaluateda Design interval of the difference between G1 vs. G3: -13% to 51%; and G2 vs. G3: panel calculated p = 0.26; panel calculated 95% confidence interval of the difference between G2 vs. G3: -13% to 49%

Complete control (with dexamethasone, 1-day chemotherapy regimen)b: G1: 25% (1/4) G2: 60% (3/5) G3: 100% (3/3) Sample size too small to calculate p-value. Sepúlveda-Vildósola 6 G1: palonosetron 0.25 mg IV Randomized 100 Complete control defined as: no emesis during first 24 hours (2008) once vs G2: ondansetron 8 controlled mg/m2/dose IV q8h while study Complete control: receiving chemotherapy G1: 92% (46/50) G2: 72% (36/50) No p-value provided. Panel calculated p = 0.017; panel calculated 95% confidence interval of the difference between G1 vs. G2: 4 % to 36% aWhere dose and/or route of administration for antiemetics is/are not listed, this information was not provided by study authors. bData obtained from personal communication with Kovacs (2016)

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Supplementary Table A4. Summary of studies used to inform recommendation 2.1-2.4: moderately emetogenic antineoplastic therapy as ranked by POGO Guideline for Classification of the Acute Emetogenic Potential of Antineoplastic Medication in Pediatric Cancer Patients First Author Antiemetic Agents Evaluateda Study Design Number of Response Definition and Results (Year of Publication) Patients PROSPECTIVE, SINGLE ARM STUDIES PALONOSETRON Nadaraja (2011) 7 palonosetron 5 µg/kg IV once Prospective 53 Complete control defined as: no emesis, no retching, observational study (138 courses of and no use of rescue medication during the first 24 5g/m2 hours after start of methotrexate infusion methotrexate) Complete control: 84% (116/138)

Complete control of nausea defined as: no nausea during the first 24 hours after start of methotrexate infusion as measured by a visual analogue scale

Complete control of nausea: 77% (106/138) aWhere dose and/or route of administration for antiemetics is/are not listed, this information was not provided by study authors.

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Supplementary Table A5. Summary of studies used to inform recommendation 2.1-2.4: moderately emetogenic antineoplastic therapy as ranked by study investigators where insufficient information available to assign emetogenic risk using the POGO Guideline for Classification of the Acute Emetogenic Potential of Antineoplastic Medication in Pediatric Cancer Patients First Author Antiemetic Agents Evaluateda Study Design Number of Patients Response Definition and Results (Year of Publication) RANDOMIZED CONTROL TRIALS APREPITANT Kang (2015) 4 G1: ondansetron + aprepitant 3 Randomized, 302 Complete control defined as: no vomiting, no retching and no use of mg/kg (max: 125 mg) PO on day double-blind, (102 patients rescue antiemetic agents during first 24 hours 1, and 2 mg/kg (max: 80 mg) PO placebo-controlled received MEC or on days 2 and 3 ± HEC) Complete control: dexamethasone IV vs G1: 70% (37/53) G2: ondansetron + placebo ± Note: 0 to 79% of patients may have received dexamethasone. dexamethasone IV G2: 55% (27/49) Note: 0 to 90% of patients may have received dexamethasone No p-value provided. Panel calculated p = 0.15; panel calculated 95% confidence interval of the difference between G1 and G2: -5% to 35% PALONOSETRON Kovacs (2016) 5 G1: palonosetron 10 µg/kg IV Double-blind, 493 Complete control defined as: no vomiting, no retching and no use of once (max: 0.75 mg/dose) ± double dummy, (339 Patients rescue antiemetic agents during first 24 hours

corticosteroid vs phase 3, non- receiving Non-inferiority of palonosetron 20 µg/kg/dose (max: 1.5 mg/dose) vs. G2: palonosetron 20 µg/kg IV inferiority study moderately ondansetron 150 µg/kg/dose (max: 10.67 mg/dose) q4h x 3 once (max: 1.5 mg/dose) ± emetogenic demonstrated corticosteroid vs chemotherapy: Complete control (MEC): G3: ondansetron 150 G1: 112 G1: 60% (67/112) µg/kg/dose (max: 10.67 G2: 116 G2: 63% (73/116) mg/dose) IV q4h x 3 ± G3: 111) G3: 67% (74/111) corticosteroid No p-value provided. G1 vs. G3: Panel calculated p=0.33; panel calculated Number of patients 95% confidence interval of the difference between G1 and G3: -7% to who received 20%; G2 vs. G3: panel calculated p=0.58; panel calculated 95% confidence corticosteroids interval of the difference between G2 and G3: -9% to 17% during acute phase is unknown. Subgroup results from patients receiving MEC: Complete control (MEC, no dexamethasone, 1-day chemotherapy b regimen) : G1: 72% (36/50) G2: 80% (40/50) G3: 73% (43/59) No p-value provided. G1 vs. G3: Panel calculated p=1; G2 vs. G3: panel aWhere dose and/or route of administration for antiemetics is/are not listed, this information was not provided by study authors. b 119 Data obtained from personal communication with Kovacs (2016)

First Author Antiemetic Agents Evaluateda Study Design Number of Patients Response Definition and Results (Year of Publication) calculated p=0.50; panel calculated 95% confidence interval of the difference between G2 and G3: -13% to 27%

Complete control (MEC, with dexamethasone, 1-day chemotherapy regimen)b: G1: 57% (4/7) G2: 88% (7/8) G3: 73% (8/11); Sample size too small to calculate p-value. PALONOSETRON Patil (2015) 8 G1: ondansetron 5 mg/m2 IV Randomized, 37 Complete control defined as: no emesis and no use of rescue antiemetic q8h crossover (160 chemotherapy agents from initiation of chemotherapy to 24 hours after therapy vs cycles; 122 HEC and G2: palonosetron 5µg/kg IV 38 MEC) Complete control: once G1: 75% (60/80) G2: 70% (56/80) Patients receiving HEC also p-value=0.479 received dexamethasone 10 mg/m2 IV once daily. PROSPECTIVE, SINGLE ARM STUDIES APREPITANT Bodge (2014) 9 aprepitant: Prospective, 11 Complete control defined as: no nausea, no vomiting, or no use of rescue <10 kg: 40 mg PO day 1 and 20 observational study (18 patient antiemetic agents during the first 24 hours mg PO days 2 and 3 encounters) 10-20 kg: 80 mg PO day 1 and Complete control: 40 mg days 2 and 3 39% (7/18) 21-40 kg: 80 mg PO on days 1-3 [<40kg: 44% (4/9) and ≥40kg: 33% (3/9)] >40 kg: 125 mg PO day 1 and 80 mg PO days 2 and 3 + ondansetron 0.45 mg/kg (max: 16 mg/dose) + dexamethasone 7mg/m2 aWhere dose and/or route of administration for antiemetics is/are not listed, this information was not provided by study authors. bData obtained from personal communication with Kovacs (2016)

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First Author Antiemetic Agents Evaluateda Study Design Number of Patients Response Definition and Results (Year of Publication) PALONOSETRON Varrasso (2013)10 palonosetron 5µg/kg/dose Prospective, single 8 Complete control defined as: no vomit, no use of rescue antiemetic [abstract] (max: 250 mcg/dose) IV arm (44 chemotherapy agents, and no more than mild nausea during first 24 hours from start of blocks) chemotherapy

Complete control: 91% (40/44)

Complete response defined as: no vomit and no rescue therapy

Complete response: 98% (43/44) RETROSPECTIVE STUDIES APREPITANT Bauters (2013) 11 aprepitant 125 mg PO day 1 and Retrospective 20 Complete control defined as: no vomiting during the first 24 hours after 80 mg PO days 2 and 3 + 5-HT3 (104 chemotherapy start of chemotherapy antagonist [tropisetron 0.2 cycles) mg/kg (max: 5 mg) IV once daily Complete control: or ondansetron 5-8 mg/m2/dose 92% (96/104 cycles) (max: 8 mg/dose) BID or [70% (14/20 patients)] granisetron 0.04 mg/kg/dose (max: 9 mg) once daily] + dexamethasone 1.5 mg/m2/dose (max: 5 mg/dose) IV once daily to BID PALONOSETRON Ripaldi (2010) 12 palonosetron 5µg/kg IV once Retrospective cohort 43 Complete control defined as: 0-1 episodes of vomiting per day and nausea study (47 bone marrow scored <1 according to NCI Common Toxicity Criteria version 2 along the transplants; 9 MEC length of the conditioning regimen and 38 HEC) Complete control: 68% (32/47) aWhere dose and/or route of administration for antiemetics is/are not listed, this information was not provided by study authors. bData obtained from personal communication with Kovacs (2016)

121

Supplementary Table A6. Clinical adverse events reported in randomized controlled trials evaluating aprepitant for CINV prophylaxis in children

First Author (Year of Publication) Bakhshi (2015)d 1 Kang (2015)a 4 Aprepitantb Placebob Aprepitante Placeboe Adverse Event N=50 N=43 N=152 N=150 ≥1 Clinical AE 79% 77% Drug-related clinical AE 3% 2% Serious drug-related clinical AE 2% 0% Anemia 17% 25% Anorexia 54% 60% Constipation 28% 28% Cough 16% 30% Diarrhea 28% 16% Febrile neutropenia 12% 18% 16% 16% Fever 18% 25% Gastritis 2% 5% Headache 40% 37% Nausea 9% 11% Neutropenia 14% 12% Neutrophil count decrease 9% 13% Platelet count decrease 8% 10% Thrombcytopenia 10% 11% Vomiting 15% 15% Drug-related AE (5 patients): hiccups, Clostridium difficile Drug-related AE (3 patients): infection, vomiting, constipation, increased alanine and aspartate Comments None of the patients developed any grade 3 or 4 AE decreased blood calcium and aminotransferase levels and potassium levels, T-wave nausea inversion aAll clinical AE are reported bPatients in aprepitant arm and placebo arm also received dexamethasone and ondansetron cFour patients in aprepitant arm, and 1 patient in placebo arm met the NCI CTCAE definition of febrile neutropenia (post-hoc analysis) dAll adverse events are as reported by patients and guardians in the acute phase, with the exception of febrile neutropenia which was evaluated from the patient health record ePatients in aprepitant arm and placebo arm also received ondansetron ± dexamethasone AE: adverse event

122

Supplementary Table A7. Clinical adverse events reported in randomized controlled trials evaluating palonosetron for CINV prophylaxis in children

First Author (Year of Publication) Sepúlveda-Vildósola (2008) 6 Tang (2013) 3 Patil (2015) 8 Kovacs (2016)b 5 Palonosetron, Palonosetron, Palonosetron Placebo Palonosetron Ondansetron Palonosetrona Ondansetrona Ondansetronc Adverse Event 10µg/kgc 20µg/kgc N=50 N=50 N=40 N=40 N=80 N=80 N=167 N=163 N=164 ≥1 Clinical AE 80% 69% 82% Drug-related clinical AE 4% 4% 4% Serious drug-related 0% 0% 0% clinical AE Abdominal distention 5% 8% Abdominal pain 0% 3% Conduction disorder <1% 0% <1% Constipation 8% 5% 9% 14% Dizziness 0% 3% 0% 1% <1% <1% 0% Dyskinesia 0% <1% 0% General disorders and administrative site <1% <1% 0% conditions None of the patients Headache reported or presented any 5% 3% 9% 6% 2% <1% 1% Musculoskeletal and AE during treatment with connective tissue palonosetron. 0% 0% <1% disorders QT prolongation 0% <1% 1% Respiratory, thoracic and 1% 0% 0% mediastinal disorders Sinus tachycardia <1% 0% 1% Skin and subcutaneous 0% 1% <1% tissue disorders No patients discontinued therapy due to drug-related AE Comments All AE resolved Only one drug-related AE was grade 3 or worse: one patient receiving palonosetron 20µg/kg experienced grade 4 infusion site pain AE: adverse event aPatients in palonosetron arm and ondansetron arm also received dexamethasone bOnly drug-related clinical AE are reported cPatients in palonosetron arm and ondansetron arm may or may not have received corticosteroids 123

Supplementary Table A8. Risk of bias for randomized controlled trials

Risk of Bias For Randomized Control Trials

If loss to follow-up is less Was the study free of selective Adequate Adequate Participants and Outcome than 20% and equally reporting? Did the authors report on Author sequence allocation personnel assessors distributed between both the outcomes they said they would generation concealment blinded? blinded? interventions then measure? Did they measure answer yes. important outcomes? 1 Bakhshi (322) Yes Yes Yes Yes Yes Yes 4 Kang (20) Yes Yes Yes Yes Yes No Sepúlveda-Vildósola Unclear No No Unclear Unclear No (174)6 3 Tang (973) Unclear Unclear Unclear Unclear Unclear Yes 8 Patil (329) Yes Unclear No No Yes Yes 5 Kovacs (2294) Yes Yes Yes Yes Yes No

124

C. Systematic review of meta-analyses evaluating palonosetron vs other 5HT3-antagonists for acute CINV prophylaxis

Search Dates and Databases: The OvidSP platform was used to search MEDLINE, Medline in Process and EMBASE for articles indexed as of March 29, 2016.

Eligibility Criteria: . Meta-analyses published in full text from 2014 to present . Published in English . Evaluated chemotherapy induced-nausea and vomiting/CIV/CIN control in acute phase with palonosetron versus other 5HT3 antagonists (with or without corticosteroids) o Acute phase is defined as starting with the first dose of chemotherapy administered during a chemotherapy block and as ending 24 hours after administration of the last dose of chemotherapy administered during the chemotherapy block OR as starting with the first dose of chemotherapy administered during the chemotherapy block and as ending 24 hours later regardless of the duration of the chemotherapy block. o A chemotherapy block is defined as a period when chemotherapy is given on consecutive days. . Complete CINV/CIV/CIN control (as defined by authors) is reported as a proportion . Search Strategy reported

Reasons for Exclusion: 1. Published before 2014 2. Not a meta-analysis 3. Does not evaluate palonosetron as an intervention versus other 5HT3 antagonists in the acute phase 4. Does not report complete CINV/CIV/CIN control (as defined by authors) as a proportion 5. Duplicate or abstract version of a fully published study 6. Search strategy not reported 7. Not in English 8. Not retrievable

125

Supplementary Figure A2. PRISMA flowchart for the systematic review of meta-analyses evaluating palonosetron vs other 5HT3-antagonists for acute CINV prophylaxis

Potentially relevant references identified (n=26)

Duplicates removed (n=9)

Citations screened by title/abstract (n=17)

Citations excluded as did not meet eligibility criteria (n=11)

Full text references retrieved for detailed evaluation (n=6)

Excluded (n=5) Not a meta-analysis (n=4) Does not evaluate palonosetron vs other 5HT3 antagonists in the acute phase (n=1)

Systematic reviews included (n=1)

126

Supplementary Table A9. Search strategies: systematic review of meta-analyses evaluating palonosetron vs other 5HT3-antagonists for acute CINV prophylaxis

MEDLINE: The search strategy for OvidSP MEDLINE (1946 to March Week 3 2016) Ovid MEDLINE(R) 1946 to March Week 3 2016 # Searches 1 (aloxi or onicit or palonosetron or "rs 25259" or "rs 25259 197" or "rs 25259-197" or rs25259 or "rs25259 197" or "rs25259-197").mp. [****palonosetron not MeSH - No registry number results****] 2 (aprepitant or emend or "l 754030" or l754030 or "mk 0869" or "mk 869" or mk0869 or mk869 or "ono 7436" or ono7436).mp. [****aprepitant not MeSH - No registry number results****] 3 Neurokinin-1 Receptor Antagonists/ 4 or/1-3 [***Drug terms****] 5 nausea/ or vomiting/ 6 (emesis or vomit* or retch* or nauseous or nausea*).mp. 7 5 or 6 8 exp neoplasms/ or exp Antineoplastic Agents/ or (cancer* or oncol* or tumour* or tumor* or malignan* or neoplas* or sarcom* or blastoma* or neuroblastoma* or leukem* or leukaem* or carcinoma* or lymphoma* or adenocarcinoma* or hodgkin* or chemotherap*).mp. 9 medical oncology/ or stem cell transplantation/ or cord blood stem cell transplantation/ or hematopoietic stem cell transplantation/ or mesenchymal stem cell transplantation/ or peripheral blood stem cell transplantation/ or bone marrow transplantation/ or transplantation, autologous/ or ((stem or marrow) adj2 transplant*).ti,ab. [****Oncology specialty or transplant terms****] 10 ((Chemotherap* adj2 induc*) or CINV).mp. or ci.fs. or chemotherap*.mp. 11 or/8-10 12 4 and 7 and 11 13 limit 12 to (meta analysis or systematic reviews) 14 (metaanalys* or "meta-analys*" or "systematic review*").ti,ab. 15 13 or (12 and 14) 16 limit 15 to yr="2014 -Current" 17 limit 16 to english language

127

MEDLINE in Process: The search strategy for OvidSP MEDLINE(R) In-Process & Other Non- Indexed Citations March 29, 2016) # Searches 1 (aloxi or onicit or palonosetron or "rs 25259" or "rs 25259 197" or "rs 25259-197" or rs25259 or "rs25259 197" or "rs25259-197").mp. [****palonosetron not MeSH - No registry number results****] 2 (aprepitant or emend or "l 754030" or l754030 or "mk 0869" or "mk 869" or mk0869 or mk869 or "ono 7436" or ono7436).mp. [****aprepitant not MeSH - No registry number results****] 3 (Neurokinin adj3 Antagonist*).mp. 4 or/1-3 5 (emesis or vomit* or retch* or nauseous or nausea* or CINV).mp. 6 (Antineoplastic* or cancer* or oncol* or tumour* or tumor* or malignan* or neoplas* or sarcom* or blastoma* or neuroblastoma* or leukem* or leukaem* or carcinoma* or lymphoma* or adenocarcinoma* or hodgkin* or chemotherap*).mp. 7 (oncology or ((autologous or stem or marrow) adj2 transplant*)).ti,ab. 8 or/6-7 9 4 and 5 and 8 10 (metaanalys* or "meta-analys*" or "systematic review*").ti,ab. 11 9 and 10 12 limit 11 to yr="2014 -Current" 13 limit 12 to english language

128

EMBASE: The search strategy for OvidSP Embase <1980 to 2016 Week 13> # Searches 1 neurokinin 1 receptor antagonist/ 2 palonosetron/ or (aloxi or onicit or palonosetron or "rs 25259" or "rs 25259 197" or "rs 25259-197" or rs25259 or "rs25259 197" or "rs25259-197").mp. 3 (135729-61-2 or 135729-62-3).rn. 4 aprepitant/ or (aprepitant or emend or "l 754030" or l754030 or "mk 0869" or "mk 869" or mk0869 or mk869 or "ono 7436" or ono7436).mp. 5 (170729-80-3 or 221350-96-5).rn. 6 or/1-5 7 "nausea and vomiting"/ or nausea/ or retching/ or vomiting/ 8 (emesis or vomit* or retch* or nauseous or nausea* or CINV).mp. 9 7 or 10 exp neoplasm/ or exp Antineoplastic Agent/ or (cancer* or oncol* or tumour* or tumor* or malignan* or neoplas* or sarcom* or blastoma* or neuroblastoma* or leukem* or leukaem* or carcinoma* or lymphoma* or adenocarcinoma* or hodgkin* or chemotherap*).mp. 11 oncologist/ or oncology/ or oncology nursing/ or oncology ward/ or stem cell transplantation/ or hematopoietic stem cell transplantation/ or allogeneic hematopoietic stem cell transplantation/ or autologous hematopoietic stem cell transplantation/ or allogeneic stem cell transplantation/ or allogeneic hematopoietic stem cell transplantation/ or allogeneic peripheral blood stem cell transplantation/ or autologous stem cell transplantation/ or autologous hematopoietic stem cell transplantation/ or autologous peripheral blood stem cell transplantation/ or cord blood stem cell transplantation/ or in utero stem cell transplantation/ or limbal stem cell transplantation/ or mesenchymal stem cell transplantation/ or neural stem cell transplantation/ or nonmyeloablative stem cell transplantation/ or peripheral blood stem cell transplantation/ or allogeneic peripheral blood stem cell transplantation/ or autologous peripheral blood stem cell transplantation/ or autotransplantation/ or bone marrow transplantation/ or allogenic bone marrow transplantation/ or autologous bone marrow transplantation/ 12 or/10-11 13 9 and 12 14 chemotherapy induced emesis/ or "chemotherapy induced nausea and vomiting"/ 15 12 or 13 16 6 and 15 17 (metaanalys* or "meta-analys*" or "systematic review*").ti,ab. 18 meta-analysis/ or systematic review/ 19 17 or 18 20 16 and 19 21 limit 20 to yr="2014 -Current" 22 limit 21 to english language 23 limit 22 to (conference abstract or conference paper or conference proceeding) 24 22 not 23

129

Supplementary Table A10. Summary of findings of systematic search for meta-analyses evaluating palonosetron vs other 5-HT3 antagonists Author Endpoint Definitions and (Year) Authors’ Conclusions Systematic Review Characteristics Efficacy – Acute Phase* Safety*

Popovic Purpose: Palonosetron vs other 5-HT3 antagonists: No constipation: Endpoint Definitions: (2014) 13 To investigate the efficacy and safety of Complete response: OR=1.32 (95% CI 1.15-1.52) OR=0.80 Complete response: no emetic episode palonosetron in relation to other 5-HT3 Complete control: OR=1.33 (95% CI 1.12-1.58) (95% CI 0.63-1.01) & no use of rescue medication antagonists for CINV prophylaxis. No emesis: OR=1.28 (95% CI 1.10-1.50) No headache: Complete control: No nausea: OR=1.21 (95% CI 1.01-1.45) OR=1.10 no emetic episode, no use of rescue Literature search end date: No rescue mediation: OR=1.58 (95% CI 0.66-3.80) (95% CI 0.84-1.44) medication & no more than mild May/June 2013 No diarrhea: nausea Subgroup analysis based on chemotherapy OR=1.82 Languages included: emetogenicity: (95% CI 0.74-4.53) Authors concluded that palonosetron Not stated HEC: No dizziness: is “more efficacious and safer than Complete response: OR=1.26 (95% CI 1.04-1.52) OR=2.15 other 5-HT3 antagonists.” Characteristics of included studies: Complete control: OR=1.23 (95% CI 1.01-1.50) (95% CI 1.05-4.41)  Number studies included: 16 No emesis: OR=1.23 (95% CI 0.99-1.52)  Number of patients randomized to No nausea: OR=1.09 (95% CI 0.88-1.35) receive palonosetron: 2,896 No rescue mediation: OR=1.58 (95% CI 0.66-3.80) Weighted mean QTc interval  Number of patients randomized to MEC: increase after treatment: Complete response: OR=1.43 (95% CI 1.10-1.86) Palonosetron: 2.45 ms receive a 5-HT antagonist other than 3 Complete control: Not able to be synthesized. Other 5-HT antagonists: 5.13 ms palonosetron: 3,187 3 No emesis: OR=1.36 (95% CI 1.06-1.74) P=0.002 No nausea: OR=1.56 (95% CI 1.11-2.18) No rescue mediation: Not able to be synthesized.

Subgroup analysis based on receipt of dexamethasone: With dexamethasone: Complete response: OR=1.14 (95% CI 0.88-1.49) Complete control: OR=1.30 (95% CI 1.03-1.63)** No emesis: OR=1.07 (95% CI 0.82-1.41) No nausea: OR=0.96 (95% CI 0.76-1.21) No rescue mediation: Not able to be synthesized. No dexamethasone: Complete response: OR=1.52 (95% CI 1.15-2.02) Complete control: Not able to be synthesized. No emesis: Not able to be synthesized. No nausea: Not able to be synthesized. No rescue mediation: Not able to be synthesized.

*OR > 1 favours palonosetron; **Complete control became statistically similar between arms after sensitivity/heterogeneity analyses; OR: odds ratio; CI: confidence interval; HEC: highly emetogenic chemotherapy; MEC: moderately emetogenic chemotherapy; ms: millisecond

130

D. Systematic review of palonosetron pharmacokinetic studies Search Dates and Databases: The OvidSP platform was used to search MEDLINE, Medline in Process and EMBASE for articles indexed as May 5, 2016.

Eligibility Criteria: . Studies reporting primary data as full papers (no date restriction) or conference abstracts (published in 2013 or more recently) . Evaluates at least one of the following pharmacokinetic parameters for palonosetron in humans of any age: Cmax, AUC, half-life, volume of distribution or clearance . No restriction by language

Reasons for Exclusion: 1. Does not report primary data 2. Conference abstract published before 2013 3. Does not evaluate palonosetron pharmacokinetics 4. Duplicate or abstract version of a fully published study 5. Not retrievable

131

Supplementary Figure A3. PRISMA flowchart for the systematic review of palonosetron pharmacokinetics

Potentially relevant references identified (n=515)

Duplicates removed (n=70)

Citations screened by title/abstract (n=445)

Citations excluded as did not meet eligibility criteria (n=419)

Full text references retrieved for detailed evaluation (n=26) Excluded (n=6) Does not report primary data (n=1) Does not report pharmacokinetics of palonosetron (n=2) Duplicate or abstract version of a fully published study (n=1) Not retrievable (n=2)

Studies included in systematic review (n=20)

132

Supplementary Table A11. Search strategies: systematic review of palonosetron pharmacokinetic studies

MEDLINE: The search strategy for OvidSP MEDLINE (1946 to April Week 4 2016) # Searches 1 (aloxi or onicit or palonosetron or "rs 25259" or "rs 25259 197" or "rs 25259-197" or rs25259 or "rs25259 197" or "rs25259-197").mp. [****palonosetron not MeSH - No registry number results****] 2 pk.fs. 3 pharmacokine*.mp. 4 ("pharmaco-kinetic*" or "pharmaco-kinesis*").mp. 5 (kinetic* or kinesis*).mp. 6 pharmacokinetics/ or absorption/ or absorption, physiological/ or gastrointestinal absorption/ or gastric absorption/ or intestinal absorption/ or intestinal reabsorption/ or oral mucosal absorption/ or rectal absorption/ or intramuscular absorption/ or ocular absorption/ or peritoneal absorption/ or renal reabsorption/ or respiratory tract absorption/ or nasal absorption/ or skin absorption/ or subcutaneous absorption/ or vaginal absorption/ or area under curve/ or biological availability/ or biotransformation/ or activation, metabolic/ or inactivation, metabolic/ or metabolic detoxication, phase i/ or metabolic detoxication, phase ii/ or cutaneous elimination/ or drug liberation/ or hepatobiliary elimination/ or intestinal elimination/ or lacrimal elimination/ or lacteal elimination/ or pulmonary elimination/ or renal elimination/ or salivary elimination/ or therapeutic equivalency/ or tissue distribution/ or toxicokinetics/ [****pharmacokinetics terms****] 7 (absorption* or absorb*).mp. 8 (excretion* or excreting or excreted or excrete or excretes).mp. 9 bl.fs. 10 de.fs. 11 se.fs. 12 me.fs 13 exp metabolism/ 14 (metabolism or metaboliz* or metabolis* or metabolic).mp. 15 or/2-14 16 1 and 15 [********] 17 limit 16 to humans 18 limit 16 to animals 19 16 not (17 or 18) 20 17 or 19

133

MEDLINE in Process: The search strategy for OvidSP MEDLINE(R) In-Process & Other Non-Indexed Citations as of May 4, 2016 # Searches 1 (aloxi or onicit or palonosetron or "rs 25259" or "rs 25259 197" or "rs 25259-197" or rs25259 or "rs25259 197" or "rs25259-197").mp. 2 pharmacokine*.mp. 3 ("pharmaco-kinetic*" or "pharmaco-kinesis*").mp. 4 (kinetic* or kinesis*).mp. 5 (bioequivalen* or activation or bioavailability or clearance or diffusion or disposition or distribution or eliminat* or "half life" or inactivat* or penetrat* or releas* or retention or concentrat* or disintegrat* or equivalen*).mp. [***pharmacokinetics terms****] 6 ((biologic* adj2 availab*) or biotransform* or detoxicat* or eliminat* or liberat* or toxicokinetic* or toxicokinesis).mp. [****pharmacokinetics terms****] 7 (accumulat* or "area under the curve" or fluctuat*).mp. 8 (absorption* or absorb*).mp. 9 (excretion* or excreting or excreted or excrete or excretes).mp. 10 (metabolism or metaboliz* or metabolis* or metabolic).mp. 11 or/2-10 12 1 and 11

134

EMBASE: The search strategy for OvidSP Embase Classic+Embase <1947 to 2016 Week 18> # Searches 1 palonosetron/ or (aloxi or onicit or palonosetron or "rs 25259" or "rs 25259 197" or "rs 25259- 197" or rs25259 or "rs25259 197" or "rs25259-197").mp. 2 (135729-61-2 or 135729-62-3).rn. 3 or/1-2 [*******] 4 pk.fs. 5 pharmacokine*.mp. 6 ("pharmaco-kinetic*" or "pharmaco-kinesis*").mp. 7 (kinetic* or kinesis*).mp. 8 pharmacokinetics/ or bioequivalence/ or drug absorption/ or drug activation/ or drug adsorption/ or exp drug bioavailability/ or exp drug clearance/ or drug dialysability/ or drug diffusion/ or drug disposition/ or drug distribution/ or drug elimination/ or drug excretion/ or exp drug half life/ or drug inactivation/ or exp drug metabolism/ or drug penetration/ or exp drug release/ or drug retention/ or plasma concentration-time curve/ or exp tablet disintegration/ or therapeutic equivalence/ [***pharmacokinetics terms****] 9 pharmacokinetic assay/ or drug metabolism assay/ 10 pharmacokinetic parameters/ or exp absorption parameters/ or accumulation ratio/ or exp area under the curve/ or concentration at steady-state/ or exp distribution parameters/ or exp drug half life/ or exp elimination parameters/ or enantiomeric ratio/ or maximum plasma concentration/ or mean residence time/ or mean transit time/ or exp metabolism parameters/ or minimum plasma concentration/ or peak-trough fluctuation/ or time to maximum plasma concentration/ 11 (absorption* or absorb*).mp. 12 (excretion* or excreting or excreted or excrete or excretes).mp. 13 exp excretion/ 14 exp metabolism/ 15 (metabolism or metaboliz* or metabolis* or metabolic).mp. 16 or/4-15 17 1 and 16 18 limit 17 to human 19 limit 17 to animal 20 17 not (18 or 19) 21 18 or 20 22 remove duplicates from 21

135

Supplementary Table A12. Summary of findings from systematic search of palonosetron pharmacokinetics. Available published evidence is limited to subjects greater than 18 years old. First author Palonosetron Pharmacokinetic Parametersa (year of Study Design, Population Palonosetron Dosing C AUC AUC t CL V publication) max 0-t 0-∞ 1/2 T d,ss 0.075 mg (~1.1 μg/kg for 70kg patient) Maemondo Study design: randomized, double-blind, dose- 0.075 mg IV infused over 30 245 ng/L 4870 20530 53.1 h 60.8 280 L (2009) 14 ranging study seconds + dexamethasone (SD 113) ng∙h/L (SD ng∙h/L [N=1] mL/min [N=1]c - G1: palonosetron 0.075 mg IV 12-16 mg IV (24 mg IV if [N=9] 4680) [N=1] [N=1] - G2: palonosetron 0.25 mg IV receiving paclitaxel) 45 [N=9] - G3: palonosetron 0.75 mg IV minutes prior

Blood Sampling Times: pre-dose, and 15 and 30 minutes and 1, 2, 4, 8, 24, 48, 72, 120 and 168 hours post- dose

Population: cancer - N: 24 (G1, 9; G2, 6; G3, 9) - Mean age: G1, 63.2 years (SD 4.9); G2, 56.5 years (SD 5.1); G3, 54.9 years (SD 9.2) - M:F=16:8 - Mean weight: G1, 54.0 kg (SD 7.6); G2, 66.2 kg (SD 17.4); G3, 52.9 kg (SD 8.1) - Ethnicity: NR - Country study was conducted: Japan

136

First author Palonosetron Pharmacokinetic Parametersa (year of Study Design, Population Palonosetron Dosing C AUC AUC t CL V publication) max 0-t 0-∞ 1/2 T d,ss 0.125 mg (~1.8 μg/kg for 70kg patient) Zhang Study design: pharmacokinetic study with 3 dose (2008) 15 levels (to test new analytical method for determination of palonosetron concentrations) - G1: palonosetron 0.125 mg IV - G2: palonosetron 0.25 mg IV - G3: palonosetron 0.5 mg IV

Blood Sampling Times: pre-dose, and 2, 5, and 10 minutes and 1, 2, 4, 6, 12, 24, 48, 96, 120, 144, 168 hours post- dose

Population: healthy 875.3 14140 16190 134 - N: 30 0.125 mg IV once (infusion 49.8 h (SD ng/L (SD ng∙h/L (SD ng∙h/L (SD mL/min NR - Mean age: rate NR) 6.8) 283.9) 3620) 3530) (SD 27.8) o Males: G1, 24 years (SD 2); G2, 23 years (SD 3); G3, 25 years (SD 2) o Females: G1, 23 years (SD 3); G2, 22 years (SD 1); G3, 22 years (SD 2) - M:F=15:15 - Mean weight: o Males: G1, 68.3 kg (SD 3.9); G2, 66.3 kg (SD 3.8), G3, 65 kg (SD 2.2) o Females: G1, 52.8 kg (SD 2.2); G2, 52.5 kg (SD 2.9); G3: 51.8 kg (SD 2.5) - Ethnicity: Chinese: 100% - Country study was conducted: China

137

First author Palonosetron Pharmacokinetic Parametersa (year of Study Design, Population Palonosetron Dosing C AUC AUC t CL V publication) max 0-t 0-∞ 1/2 T d,ss Yang (2012) Study design: pharmacokinetic study (to test new 16 analytical method for determination of palonosetron concentrations)

Blood Sampling Times: pre-dose, and 1, 5, 15, and 30 minutes and 1, 2, 4, 6, 12, 24, 48, 72, 96, 120, 144 and 168 hours post- dose 15700 16600 0.125 mg IV once (infusion 875 ng/L 39.5 h (SD ng∙h/L (SD ng∙h/L (SD NR NR Population: healthy time NR) (SD 173) 4.8) 3000) 3000) - N: 6 - Mean age: NR (range: NR ) - M:F=NR - Mean weight: NR (range: NR) - Ethnicity: Chinese: 100% - Country study was conducted: China

0.25 mg (~3.6 μg/kg for 70kg patient) Shah (2005) Study design: single-centre, open-label, randomized, 34800 2060 ng/L 17 two-way crossover trial ng∙h/L (CV% 61) 136 0.25 mg IV infused over 10 (CV% 33) 43.0 h 442.3 L NR mL/min Blood Sampling Times: pre-dose, and 1, 3, 5, 15, and seconds (CV% 26) (CV% 36) 1700 (CV% 43) 30 minutes and 1, 2, 4, 6, 12, 24, 48, 72, 96, 120, 144 32900 ng/Lb and 168 hours post- dose ng∙h/Lb

Population: healthy non-smoking patients 34300 - N: 12 0.25 mg IV infused over 10 2360 ng/L ng∙h/L - mean age: 29.9 years (range: NR, 18-45 years seconds + aprepitant 125 mg (CV% 104) 130 (CV% 27) 40.0 h 410.9 L eligible) PO day 1 (30 minutes prior), NR mL/min (CV% 26) (CV% 23) - M:F=7:5 followed by 80 mg on days 2 1680 (CV% 28) 33200 - Mean weight: NR and 3 ng/Lb ng∙h/Lb - Ethnicity: White: 9/12 (75%) - Country study was conducted: United States Hunt Study design: phase I, single-center, double-blind, 0.25 mg 7680 (2005) 18 randomized, placebo-controlled, parallel safety and IV once 1030 ng/L ng∙h/L pharmacokinetic study daily Day (CV% 84) (CV% 16)f Male NR NR NR NR bolus for 1 Blood Sampling Times: pre-dose, and 1, 3, 5, 15, and 3 days 781 ng/Lb 7600 30 minutes and 1, 2, 4, 6, 12, and 24 hours post-dose (infusion ng∙h/Lb

138

First author Palonosetron Pharmacokinetic Parametersa (year of Study Design, Population Palonosetron Dosing C AUC AUC t CL V publication) max 0-t 0-∞ 1/2 T d,ss on days 1-3 and 48, 96, 120, 144 and 168 hours post- rate NR) 10100 1220 ng/L day 3 dose ng∙h/L (CV% 42) (CV% 19)f Female NR NR NR NR Population: 1150 - N: 16 (12 palonosetron, 4 placebo) 9700 ng/Lb - Mean age, palonosetron arm: 27.5 years (SD ng∙h/Lb 8.2) 8900 - M:F=8:8 1130 ng/L ng∙h/L - Mean weight, palonosetron arm: 68.7 kg (SD (CV% 61) (CV% 22)f Combined NR NR NR NR 10.6) - Ethnicity: White: 75% (12/16) 946 ng/Lb 8700 - Country study was conducted: United States ng∙h/Lb 16900 2250 ng/L ng∙h/L (CV% 59) (CV% 25)f 42.3 h Male NR NR NR (CV% 25) 1860 16500 ng/Lb ng∙h/Lb 19600 2610 ng/L ng∙h/L (CV% 38) Day (CV% 12)f 43.3 h Female NR NR NR 3 (CV% 27) 2400 19500 ng/Lb ng∙h/Lb 18200 2430 ng/L ng∙h/L (CV% 47) (CV% 19)f 42.8 h Combined NR NR NR (CV% 25) 2120 17900 ng/Lb ng∙h/Lb Shah (2006) Study design: phase I, single-center, open-label, 17500 20700 19 randomized, 2-way crossover study 919 ng/L ng∙h/L ng∙h/L 214 611 L 0.25 mg IV infused over 15 (CV% 44) (CV% 28) (CV% 25) 37 h (CV% mL/min (CV% 24) Blood Sampling Times: minutes 24) (CV% 26) - 15 minute infusion: pre-dose, and 5, 10 15, 18, 851 ng/Lb 16900 20100 20, and 30 minutes and 1, 2, 4, 6, 12, 24, 48, 96, ng∙h/Lb ng∙h/Lb

139

First author Palonosetron Pharmacokinetic Parametersa (year of Study Design, Population Palonosetron Dosing C AUC AUC t CL V publication) max 0-t 0-∞ 1/2 T d,ss 120, 144, and 168 hours post- dose (time 0 = start of infusion) - 30 second infusion: pre-dose, 1, 3, 5, 15, and 30 minutes and 1, 2, 4, 6, 12, 24, 48, 72, 96, 120, 144 and 168 hours post-dose 17700 20700 1650 ng/L ng∙h/L ng∙h/L 554 L (CV% 60) 209 Population: healthy patients 0.25 mg IV infused over 30 (CV% 25) (CV% 21) 33.3 h (CV% 30) mL/min - N: 12 (11 completed study) seconds (CV% 30) 1380 (CV% 21) - Mean age: 28.3 years (range: NR, 18-45 years 17300 20300 ng/Lb eligible) ng∙h/Lb ng∙h/Lb - M:F=10:2 - Mean weight: 70.2 kg (range: 47.2-85.7 kg) - Ethnicity: White: 8/12 (66.7%) - Country study was conducted: United States

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First author Palonosetron Pharmacokinetic Parametersa (year of Study Design, Population Palonosetron Dosing C AUC AUC t CL V publication) max 0-t 0-∞ 1/2 T d,ss Ding (2007) Study design: pharmacokinetic study (to test new 23800 26800 162 2070 ng/L 52.2 h (SD 711 L (SD 20 analytical method for determination of Male ng∙h/L (SD ng∙h/L (SD mL/min (SD 740) 16.8) 208) palonosetron concentrations) 4300) 5400) (SD 36.7)

Blood Sampling Times: pre-dose, and 1, 5, 15 and 30 minutes and 1, 2, 4, 6, 12, 24, 48, 72, 120, 144 and 168 hours post- dose 0.25 mg IV infused within 27000 29100 153 Population: healthy 1 minute 2370 ng/L 42.3 h (SD 557 L (SD Female ng∙h/L (SD ng∙h/L (SD mL/min - N: 10 (SD 1030) 4.3) 158) 7100) 8300) (SD 43.3) - Mean age: NR (range: NR ) - M:F=5:5 - Mean weight: NR (range: NR) - Ethnicity: Chinese: 100% - Country study was conducted: China Einhorn Study design: phase 2, open-label, multicenter 1270 1920 ng/L (2007) 21 study to evaluate alternate day dosing of ng∙h/L Day 1 (CV%57- NR NR NR NR palonosetron (Day 1, 3 and 5) 0.25 mg IV (CV%32- 84) infused over 30 39)e Blood Sampling Times: pre-dose, and 1-2 and 30 seconds on Day 1550 2500 ng/L minutes post- dose + at the end of day’s CT 1, 3 and 5 + ng∙h/L Day 3 (CV%57- NR NR NR NR dexamethasone (CV%32- 84) Population: testicular cancer receiving cisplatin- 20 mg IV days 1 39)e based chemotherapy and 2 and 8 mg - N: 11 PO BID on days 1680 - Mean age: 33.6 years (SD 8.43) 6 and 7 and 4 2580 ng/L ng∙h/L - M:F=11:0 mg PO BID on Day 5 (CV%57- NR NR NR NR (CV%32- - Mean weight: NR (range: NR) day 8 84) 39)e - Ethnicity: White: 100% - Country study was conducted: United States Zhang Study design: pharmacokinetic study with 3 dose (2008) 15 levels (to test new analytical method for determination of palonosetron concentrations) - G1: palonosetron 0.125 mg IV 33880 36350 118 0.25 mg IV once (infusion 1632 ng/L 45.5 h (SD - G2: palonosetron 0.25 mg IV ng∙h/L (SD ng∙h/L (SD mL/min NR rate NR) (SD 594) 8.2) - G3: palonosetron 0.5 mg IV 6180) 6320) (SD 21.7)

Blood Sampling Times: pre-dose, and 2, 5, and 10 minutes and 1, 2, 4, 6, 12, 24, 48, 96, 120, 144, 168 141

First author Palonosetron Pharmacokinetic Parametersa (year of Study Design, Population Palonosetron Dosing C AUC AUC t CL V publication) max 0-t 0-∞ 1/2 T d,ss hours post- dose

Population: healthy - N: 30 - Mean age: o Males: G1, 24 years (SD 2); G2, 23 years (SD 3); G3, 25 years (SD 2) o Females: G1, 23 years (SD 3); G2, 22 years (SD 1); G3, 22 years (SD 2) - M:F=15:15 - Mean weight: o Males: G1, 68.3 kg (SD 3.9); G2, 66.3 kg (SD 3.8), G3, 65 kg (SD 2.2) o Females: G1, 52.8 kg (SD 2.2); G2, 52.5 kg (SD 2.9); G3: 51.8 kg (SD 2.5) - Ethnicity: Chinese: 100% - Country study was conducted: China Maemondo Study design: randomized, double-blind, dose- (2009) 14 ranging study - G1: palonosetron 0.075 mg IV - G2: palonosetron 0.25 mg IV - G3: palonosetron 0.75 mg IV

Blood Sampling Times: pre-dose, and 15 and 30 minutes and 1, 2, 4, 8, 24, 48, 72, 120 and 168 0.25 mg IV infused over 30 14300 20160 213 hours post- dose seconds + dexamethasone 625 ng/L 43.3 h (SD 766 L (SD ng∙h/L (SD ng∙h/L (SD mL/min 12-16 mg IV (24 mg IV if (SD 72) 13.7) 141) 3240) 3780) (SD 42.8) Population: cancer receiving paclitaxel) 45 [N=6] [N=5] [N=1]c [N=6] [N=5] [N=5] - N: 24 (G1, 9; G2, 6; G3, 9) minutes prior - Mean age: G1, 63.2 years (SD 4.9); G2, 56.5 years (SD 5.1); G3, 54.9 years (SD 9.2) - M:F=16:8 - Mean weight: G1, 54.0 kg (SD 7.6); G2, 66.2 kg (SD 17.4); G3, 52.9 kg (SD 8.1) - Ethnicity: NR - Country study was conducted: Japan

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First author Palonosetron Pharmacokinetic Parametersa (year of Study Design, Population Palonosetron Dosing C AUC AUC t CL V publication) max 0-t 0-∞ 1/2 T d,ss Dai (2009) Study design: PK study 22 Population: healthy - N: 12 1.54 (SD 11.39 (SD 14.44 (SD 5.68 (SD 0.25 mg IV (infusion time 41.90 (SD 18.75 (SD - Mean age: 26.8 years (SD 5) 0.46) 4.94) 5.45) 2.56) NR) 11.90 h) 4.28) L/kg - M:F=6:6 ng/mL h∙ng/mL h∙ng/mL ml∙min/kg - Mean weight: NR (range: NR) - Ethnicity: Chinese: 100% - Country study was conducted: China Li (2012) 23 Study design: pharmacokinetic study (to test new analytical method for determination of palonosetron concentrations)

Blood Sampling Times: pre-dose, and 5, 10, 20, and 30 minutes and 1, 2, 4, 8, 12, 24, 48, 72, 96, 120, 144 and 168 hours post- dose 19160 19930 234.5 0.25 mg IV infused over 5 1810 ng/L 35.62 h 724.13 L ng∙h/L (SD ng∙h/L (SD mL/min minutes (SD 1124) (SD 5.5) (SD 250.9) Population: healthy 5650) 5910) (SD 67.2) - N: 10 - Mean age: NR (range: NR) - M:F=5:5 - Mean weight: NR (range: NR) - Ethnicity: NR - Country study was conducted: China Sun (2012) Study design: open-label, randomized PK study 24 Population: healthy subjects - N: 24 24.3 25.0 0.25 mg IV infused over 2 5.57 µg/L 31.0 h (SD 11.0 L/h 495 L (SD - Mean age: NR (range: 18-40 years) µg∙h/L (SD µg∙h/L (SD minutes (SD 2.97) 5.6) (SD 3.6) 208) - M:F=NR 7.6) 8.0) - Mean weight: - Ethnicity: NR - Country study was conducted: China

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First author Palonosetron Pharmacokinetic Parametersa (year of Study Design, Population Palonosetron Dosing C AUC AUC t CL V publication) max 0-t 0-∞ 1/2 T d,ss Shi (2013) Study design: randomized, crossover bioavailability 25 study and PK study

Population: healthy 0.58 35 45 - N: 24 74 h (SD 7.7 L/h (SD 806 L (SD 0.25 mg PO ng/mL (SD ng∙h/mL ng∙h/mL - Mean age: 35 years (SD 3) 18) 2.1)g 265)g 0.20) (SD 10) (SD 16) - M:F=12:12 - Mean weight: 60 kg (range: NR) - Ethnicity: Chinese: 100% - Country study was conducted: China Sadaba Study design: randomized, crossover study to 11880 14100 0.25 mg IV infused over 30 12.71 h (2014) 26 evaluate bioavailability between palonosetron IV ng/L (SD ng∙h/L NR NR NR seconds (SD 10.21) vs SC 7380) (6730)

Blood Sampling Times: pre-dose, and 10, 15, 30, 45 and 60 minutes and 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post- dose

Population: patients receiving platinum-based 12680 1910 ng/L 14.68 h chemotherapy 0.25 mg SC (in abdomen) ng∙h/L (SD NR NR NR (SD 1090) (SD 9.79) - N: 25 6700) - Mean age: 58 years (range: 31-74 years) - M:F=18:7 - Mean weight: 77 kg (50.8-121 kg) - Ethnicity: NR - Country study was conducted: Spain

144

First author Palonosetron Pharmacokinetic Parametersa (year of Study Design, Population Palonosetron Dosing C AUC AUC t CL V publication) max 0-t 0-∞ 1/2 T d,ss 0.5 mg (~7.1 μg/kg for 70kg patient) Zhang Study design: pharmacokinetic study with 3 dose (2008) 15 levels (to test new analytical method for determination of palonosetron concentrations) - G1: palonosetron 0.125 mg IV - G2: palonosetron 0.25 mg IV - G3: palonosetron 0.5 mg IV

Blood Sampling Times: pre-dose, and 2, 5, and 10 minutes and 1, 2, 4, 6, 12, 24, 48, 96, 120, 144, 168 hours post- dose

Population: healthy 48760 53430 198 - N: 30 0.5 mg IV once (infusion rate 3301 ng/L 49.5 h (SD ng∙h/L (SD ng∙h/L (SD mL/min NR - Mean age: NR) (SD 1359) 13.4) 26690) 29260) (SD 93) o Males: G1, 24 years (SD 2); G2, 23 years (SD 3); G3, 25 years (SD 2) o Females: G1, 23 years (SD 3); G2, 22 years (SD 1); G3, 22 years (SD 2) - M:F=15:15 - Mean weight: o Males: G1, 68.3 kg (SD 3.9); G2, 66.3 kg (SD 3.8), G3, 65 kg (SD 2.2) o Females: G1, 52.8 kg (SD 2.2); G2, 52.5 kg (SD 2.9); G3: 51.8 kg (SD 2.5) - Ethnicity: Chinese: 100% - Country study was conducted: China Sun (2012) Study design: open-label, randomized PK study 24 Population: healthy - N: 24 48.3 50.2 - Mean age: NR (range: 18-40 years) 0.5 mg IV infused over 2 6.84 µg/L 33.5 h (SD 11.0 L/h 513 L (SD µg∙h/L (SD µg∙h/L (SD - M:F=NR minutes (SD 5.48) 5.6) (SD 4.1) 138) 14.6) 16.1) - Mean weight: - Ethnicity: NR - Country study was conducted: China

145

First author Palonosetron Pharmacokinetic Parametersa (year of Study Design, Population Palonosetron Dosing C AUC AUC t CL V publication) max 0-t 0-∞ 1/2 T d,ss Calcagnile Study design: pharmacokinetic evaluation from 3 32564 37524 0.5 mg PO + netupitant 300 775.3 ng/L (2013) randomized, open-label, crossover drug- ng∙h/L (SD ng∙h/L (SD NR NR NR mg PO (SD 185.0) [abstract] 27 interaction (DDI) studies 7459) 9577) - G1: Netupitant/ palonosetron (NEPA) DDI 0.5 mg PO + netupitant 300 36899 40910 898.7 ng/L study (2 period crossover) mg PO + ketoconazole 400 ng∙h/L (SD ng∙h/L (SD NR NR NR (SD 220.1) - G2: NEPA/ketoconazole-rifampicin DDI study mg 8667) 9261) (2 period balanced crossover, patients receive ketoconazole or rifampicin for one block and NEPA for the alternate block) - G3: NEPA/oral contraceptive DDI study (2 32371 35714 0.5 mg PO + netupitant 300 772.2 ng/L period crossover) [Palonosetron PK results ng∙h/L (SD ng∙h/L (SD NR NR NR mg PO (SD 206.0) not reported] 13055) 13467)

Blood Sampling Times: - G2: pre-dose, and 1, 2, 3 4, 4.5, 5, 5.5 6, 8, 12, 24, 48, 72, 96, 120, 144 and 192 hours post- dose

G2: Population: healthy adults 25557 28354 d 0.5 mg PO + netupitant 300 654.5 ng/L - N: 36 ng∙h/L (SD ng∙h/L (SD NR NR NR mg PO + rifampicin 600 mg (SD 138.4) - Mean age: 45.56 years (range: 32-55 years ) 7679) 7851) - M:F=21:15 - Mean weight: 74.70 kg (range: 52.3-101.0 kg) - Ethnicity: NR - Country study was conducted: Germany Shi (2013) Study design: randomized, crossover bioavailability 0.82 43 47 12.4 L/h 787 L (SD 25 study and PK study 0.5 mg PO ng/mL (SD ng∙h/mL ng∙h/mL 44 h (SD 9) (SD 3.1)g 248)g 0.17) (SD 12) (SD 14) Population: healthy - N: 24 - Mean age: 35 years (SD 3) 5.58 40 47 54 h (SD 13.3 L/h 989 L (SD - M:F=12:12 0.5 mg IV ng/mL (SD ng∙h/mL ng∙h/mL 18) (SD 3.4)g 281)g - Mean weight: 60 kg (range: NR) 2.66) (SD 12) (SD 16) - Ethnicity: Chinese: 100% - Country study was conducted: China Spinelli Study design: phase I, randomized, double-blind, 821.6 ng/L 22641 0.5 mg PO once + netupitant (2014) 28 double-dummy, parallel-group, placebo- and open- (SD ng∙h/L (SD NR NR NR NR PO 200 mg once label positively controlled study to determine 1.277)b 1.241)b 146

First author Palonosetron Pharmacokinetic Parametersa (year of Study Design, Population Palonosetron Dosing C AUC AUC t CL V publication) max 0-t 0-∞ 1/2 T d,ss whether combined administration of different doses of netupitant + palonosetron prolongs QTc more than placebo

Blood Sampling Times: 1, 2, 4, 5, 6, 7,8,10, 12,14,16,18,23.5, 30, 36, 42 and 47.5 hours post- dose

Population: healthy - N: 197 (195 completed study, 98 received palonosetron) - Mean age: o Palonosetron 0.5 mg: 33.6 years (range: 21-44 years) o Palonosetron 1.5 mg: 32.8 years (range: 19-45 years) - M:F=106:91 (54:44 receiving palonosetron) - Mean weight: NR (range: NR) - Ethnicity: NR - Country study was conducted: Germany Calcagnile Study design: single-center, open-label, 29760 30371 767.9 ng/L (2015) 29 randomized, 2-way crossover study (adults, fed vs ng∙h/L (SD ng∙h/L (SD 38.9 h (SD (SD 159.2) fasted) and parallel study (elderly, fasted) Adults 6539) 8416) 11.3)

Fed NR NR 752.5 Blood Sampling Times: pre-dose, and 1, 2, 3, 4, 4.5, (N=22) 28989 29198 37.6 hb ng/Lb (SD 5, 5.5, 6, 8, 12, 24, 48, 72, 96, 120, 144 and 192 ng∙h/Lb ng∙h/Lb (SD 1.29) 0.5 mg PO + 1.23) hours post- dose (SD 1.28) (SD 1.34) netupitant 300 30371 33645 mg PO once 785.6 ng/L 36.9 h (SD Population: healthy ng∙h/L (SD ng∙h/L (SD (SD 223.5) 8.70) - N: 36 (34 completed study) Adults 8416) 8974)

- Mean age (range): Fasted NR NR 760.1 35.9 hb o Adults Fed followed by fasted: 35.1 years (N=22) 29198 32445 ng/Lb (SD (SD 1.26) (range: 23-44) ng∙h/Lb ng∙h/Lb 1.29) o Adults Fasted followed by Fed: 34.1 years (SD 1.34) (SD 1.33)

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First author Palonosetron Pharmacokinetic Parametersa (year of Study Design, Population Palonosetron Dosing C AUC AUC t CL V publication) max 0-t 0-∞ 1/2 T d,ss (range: 22-45) 39577 45047 o Elderly Fasted: 70.1 years (range: 66-79) 851.2 ng/L 56.3 h (SD ng∙h/L (SD ng∙h/L (SD - M:F=22:14 (SD 146.3) 14.1) Elderly 6617) 7903) - Mean weight: NR (range: NR) Fasted NR NR - Ethnicity: NR 839.5 54.6 hb (N=22) 39069 44414 - Country study was conducted: Germany ng/Lb (SD (SD 1.30) ng∙h/Lb ng∙h/Lb 1.19) (SD 1.18) (SD 1.19)

0.75 mg (~10.7 μg/kg for 70kg patient) Maemondo Study design: randomized, double-blind, dose- (2009) 14 ranging study - G1: palonosetron 0.075 mg IV - G2: palonosetron 0.25 mg IV - G3: palonosetron 0.75 mg IV

Blood Sampling Times: pre-dose, and 15 and 30 minutes and 1, 2, 4, 8, 24, 48, 72, 120 and 168 0.75 mg IV infused over 30 59500 66380 202 hours post- dose seconds + dexamethasone 2277 ng/L 41.6 h (SD 695 L (SD ng∙h/L (SD ng∙h/L (SD mL/min 12-16 mg IV (24 mg IV if (SD 589) 13.1) 191) 18220) 19280) (SD 55.7) Population: cancer receiving paclitaxel) 45 [N=9] [N=9] [N=1]c [N=9] [N=9] [N=9] - N: 24 (G1, 9; G2, 6; G3, 9) minutes prior - Mean age: G1, 63.2 years (SD 4.9); G2, 56.5 years (SD 5.1); G3, 54.9 years (SD 9.2) - M:F=16:8 - Mean weight: G1, 54.0 kg (SD 7.6); G2, 66.2 kg (SD 17.4); G3, 52.9 kg (SD 8.1) - Ethnicity: NR - Country study was conducted: Japan Sun (2012) Study design: open-label, randomized PK study 24 Population: healthy - N: 24 74.7 76.8 0.75 mg IV infused over 2 9.75 µg/L 31.1 h (SD 10.7 L/h 463 L (SD - Mean age: NR (range: 18-40 years) µg∙h/L (SD µg∙h/L (SD minutes (SD 5.78) 5.0) (SD 3.1) 91) - M:F=NR 25.4) 27.2) - Mean weight: - Ethnicity: NR - Country study was conducted: China

148

First author Palonosetron Pharmacokinetic Parametersa (year of Study Design, Population Palonosetron Dosing C AUC AUC t CL V publication) max 0-t 0-∞ 1/2 T d,ss Calcagnile Study design: pharmacokinetic evaluation from 3 1638.4 67415 70813 (2013) randomized, open-label, crossover drug- 0.75 mg ng/L (SD ng∙h/L (SD ng∙h/L (SD NR NR NR [abstract] 27 interaction (DDI) studies 415.5) 19554) 20415) - G1: Netupitant/ palonosetron (NEPA) DDI study (2 period crossover) - G2: NEPA/ketoconazole-rifampicin DDI study (2 period balanced crossover, patients receive ketoconazole or rifampicin for one block and NEPA for the alternate block) - G3: NEPA/oral contraceptive DDI study (2 period crossover) [Palonosetron PK results not reported]

Blood Sampling Times: - G1: pre-dose, and 1, 2, 3 4, 4.5, 5, 5.5 6, 8, 12, 1863.1 74230 77254 24, 48, 72, 96, 120, 144, 168, 192, 216, and 0.75 mg + netupitant 450 mg ng/L (SD ng∙h/L (SD ng∙h/L (SD NR NR NR 240 hours post- dose 487.1) 24866) 25402) - G2: pre-dose, and 1, 2, 3 4, 4.5, 5, 5.5 6, 8, 12, 24, 48, 72, 96, 120, 144 and 192 hours post- dose

G1 Population: healthy adults - N: 18 - Mean age: 26 years (range: 18-43 years) - M:F=9:9 - Mean weight: 70.2 kg (range: 44.0-88.0 kg) - Ethnicity: NR - Country study was conducted: Sweden Shi (2013) Study design: randomized, crossover bioavailability 25 study and PK study

Population: healthy 1.95 82 88 - N: 24 10.6 L/h 605 L (SD 0.75 mg PO ng/mL (SD ng∙h/mL ng∙h/mL 41 h (SD 9) - Mean age: 35 years (SD 3) (SD 4.0)g 201)g 0.94) (SD 34) (SD 39) - M:F=12:12 - Mean weight: 60 kg (range: NR) - Ethnicity: Chinese: 100% - Country study was conducted: China 149

First author Palonosetron Pharmacokinetic Parametersa (year of Study Design, Population Palonosetron Dosing C AUC AUC t CL V publication) max 0-t 0-∞ 1/2 T d,ss Ikari (2014) Study design: pharmacokinetic study evaluating 42400 76000 176 2050 ng/L 39.4 h (SD 580 L (SD 30 palonosetron PK parameters on day 1 and day 3 of ng∙h/L (SD ng∙h/L (SD mL/min Day 1 (SD 630, 8.5, CV% 132,CV% chemotherapy block 9000, CV 20500, CV (SD 53, CV% 30.9) 21.5) 22.7)c 21.1%) 27.0%) CV% 29.9) Blood Sampling Times: 15 and 30 minutes and 1, 4, 8 and 24 post- first dose and pre-second dose + 15 and 30 minutes and 1, 4, 8, 24 and 48 hours 0.75 mg IV on post-second dose Day 1 and Day 58300 108900 3 2900 ng/L 42.5 h (SD Population: hematologic malignancy ng∙h/L (SD ng∙h/L (SD Day 3 (SD 990, 5.9, CV% NR NR - N: 6 13500, CV 22200, CV CV% 34.2) 13.8) - Median age: 57.5 years (range: 50-67 years) 23.2%) 20.4%) - M:F=3:3 - Mean weight: NR - Ethnicity: Japanese: 100% - Country study was conducted: Japan

150

First author Palonosetron Pharmacokinetic Parametersa (year of Study Design, Population Palonosetron Dosing C AUC AUC t CL V publication) max 0-t 0-∞ 1/2 T d,ss 1.5 mg (~21.4 μg/kg for 70kg patient) Spinelli Study design: phase I, randomized, double-blind, (2014) 28 double-dummy, parallel-group, placebo- and open- label positively controlled study to determine whether combined administration of different doses of netupitant + palonosetron prolongs QTc more than placebo

Blood Sampling Times: 1, 2, 4, 5, 6, 7,8,10, 12,14,16,18,23.5, 30, 36, 42 and 47.5 hours post- dose

2588 67918 Population: healthy 1.5 mg PO once + netupitant ng/L(SD ng∙h/L (SD NR NR NR NR - N: 197 (195 completed study, 98 received PO 600 mg once 1.239)b 1.210)b palonosetron) - Mean age: o Palonosetron 0.5mg: 33.6 years (range: 21-44 years) o Palonosetron 1.5 mg: 32.8 years (range: 19-45 years) - M:F=106:91 (54:44 receiving palonosetron) - Mean weight: NR (range: NR) - Ethnicity: NR - Country study was conducted: Germany

151

First author Palonosetron Pharmacokinetic Parametersa (year of Study Design, Population Palonosetron Dosing C AUC AUC t CL V publication) max 0-t 0-∞ 1/2 T d,ss 0.3 µg/kg Stoltz Study design: pharmacokinetic evaluation of (2004) 31 palonosetron based on 2 phase I, randomized, double-blind, placebo controlled, dose-ascending studies - Study 1: palonosetron dose infused over 5 minutes o 9 dose levels: 0.3, 1, 3, 10, 20, 30, 45, 60 and 90 µg/kg IV once - Study 2: palonosetron dose given as IV bolus infused over 30 seconds o 4 dose levels: 3, 10, 30 and 90 µg/kg IV once 1.11 3.85 L/kg mL/min/kg 5800 (SD 0.645) Study 1 0.3 µg/kg [N=6] IV once, 114 ng/L 54.1 h (SD (SD 0.652) NR ng∙h/L (SD Blood Sampling Times: pre-dose, and 5, 10, 15, 30, infused over 5 minutes (SD 63) 36.6) 3460) 323 L and 45 minutes and 1, 1.5, 2, 4, 6, 8, 12, 24, 36, 93 mL/min (SD 54)g and 48 hours post- dose and at 72 and 168 hours (SD 55)g post-dose in subjects receiving doses ≥10µg/kg

Population: healthy males - N: 80 (60 included in PK analysis) - Mean age: o 0.3 µg/kg: 32 years (range: 21-41 years) - M:F=80:0 - Mean weight: o 0.3 µg/kg: 84 kg (range: 65-96 kg) - Ethnicity: White: 90%, Asian: 4%, Black: 6% - Country study was conducted: United States 1 µg/kg Stoltz Study design: pharmacokinetic evaluation of (2004) 31 palonosetron based on 2 phase I, randomized, 1.89 double-blind, placebo controlled, dose-ascending mL/min/kg 5.31 L/kg studies 9350 (SD 0.456) (SD 2.35) 1 µg/kg [N=6] IV once, 349 ng/L 33.7 h (SD - Study 1: palonosetron dose infused over 5 NR ng∙h/L (SD infused over 5 minutes (SD 206) 16.8) minutes 2590) 149 419 L o 9 dose levels: 0.3, 1, 3, 10, 20, mL/min (SD 186)g 30, 45, 60 and 90 µg/kg IV once (SD 36)g - Study 2: palonosetron dose given as IV bolus 152

First author Palonosetron Pharmacokinetic Parametersa (year of Study Design, Population Palonosetron Dosing C AUC AUC t CL V publication) max 0-t 0-∞ 1/2 T d,ss infused over 30 seconds o 4 dose levels: 3, 10, 30 and 90 µg/kg IV once

Study 1 Blood Sampling Times: pre-dose, and 5, 10, 15, 30, and 45 minutes and 1, 1.5, 2, 4, 6, 8, 12, 24, 36, and 48 hours post- dose and at 72 and 168 hours post-dose in subjects receiving doses ≥10µg/kg

Population: healthy males - N: 80 (60 included in PK analysis) - Mean age: o 1 µg/kg: 31 years (range: 18-44 years) - M:F=80:0 - Mean weight: o 1 µg/kg: 79 kg (range: 54-94 kg) - Ethnicity: White: 90%, Asian: 4%, Black: 6% - Country study was conducted: United States Eisenberg Study design: randomized, double-blind, (2004) 32 multicenter, parallel-design - 5 dose levels: 1, 3, 10, 30 and 90 µg/kg IV once

Blood Sampling Times: pre-dose, and 15 and 30 minutes and 1, 2, 3, 4, 5, 6, 12, 24, 48, 72, 120, and 168 hours post- dose

4170 13800 1.51 Population: chemotherapy-naïve cancer patients 1 µg/kg [N=6] IV Infused 890 ng/L 128 h (SD 12.5 L/kg ng∙h/L (SD ng∙h/L (SD mL/min/kg receiving cisplatin-based chemotherapy over 30 seconds (SD 920) f 93.8) (SD 4.19) 4970) 7580) (SD 0.70) - N: 161 (35 included in PK analysis) - Mean age: 60 years (range: 23-79 years) - M:F=129:32 - Mean weight: 74 kg (range: 39-132 kg) - Ethnicity: White: 81%; Black: 13%; Hispanic: 4%; Asian: 1%; Other: 1% - Country study was conducted: United States

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First author Palonosetron Pharmacokinetic Parametersa (year of Study Design, Population Palonosetron Dosing C AUC AUC t CL V publication) max 0-t 0-∞ 1/2 T d,ss 3 µg/kg Stoltz Study design: pharmacokinetic evaluation of (2004) 31 palonosetron based on 2 phase I, randomized, double-blind, placebo controlled, dose-ascending studies - Study 1: palonosetron dose infused over 5 minutes o 9 dose levels: 0.3, 1, 3, 10, 20, 30, 45, 60 and 90 µg/kg IV once - Study 2: palonosetron dose given as IV bolus infused over 30 seconds o 4 dose levels: 3, 10, 30 and 90 1.81 µg/kg IV once mL/min/kg 6.88 L/kg

29800 (SD 0.547) (SD 0.874) Study 1 3 µg/kg [N=6] IV, infused 918 ng/L 47.2 h (SD NR ng∙h/L (SD Blood Sampling Times: pre-dose, and 5, 10, 15, 30, over 5 minutes (SD 250) 14.7) 9020) 145 550 L and 45 minutes and 1, 1.5, 2, 4, 6, 8, 12, 24, 36, mL/min (SD 70)g and 48 hours post- dose and at 72 and 168 hours (SD 44)g post-dose in subjects receiving doses ≥10µg/kg

Population: healthy males - N: 80 (60 included in PK analysis) - Mean age: o 3 µg/kg: 27 years (range: 18-32 years) - M:F=80:0 - Mean weight: o 3 µg/kg: 80 kg (range: 66-95 kg) - Ethnicity: White: 90%; Asian: 4%; Black: 6% - Country study was conducted: United States

154

First author Palonosetron Pharmacokinetic Parametersa (year of Study Design, Population Palonosetron Dosing C AUC AUC t CL V publication) max 0-t 0-∞ 1/2 T d,ss Study 2

Blood Sampling Times: pre-dose, and 1, 5, 15, and 30 minutes and 1, 2, 4, 6, 12, 24, 48, 72, 120, 144 and 168 hours post- dose 3.50 mL/min/kg 8.81 L/kg Population: healthy males 15200 (SD 0.817) (SD 1.38) 3 µg/kg [N=6] IV, infused 4680 ng/L 30.8 h (SD - N: 32 (24 included in PK analysis) NR ng∙h/L over 30 seconds (SD 4680) 9.22) - Mean age: (SD 4580) 214 537 L o 3 µg/kg: 23 years (range: 20-28 years) mL/min (SD 84)g - M:F=32:0 (SD 50)g - Mean weight: o 3 µg/kg: 61 kg (range: 55-72 kg) - Ethnicity: Asian: 100% - Country study was conducted: Japan Eisenberg Study design: randomized, double-blind, 32(2004) multicenter, parallel-design - 5 dose levels: 1, 3, 10, 30 and 90 µg/kg IV once

Blood Sampling Times: pre-dose, and 15 and 30 minutes and 1, 2, 3, 4, 5, 6, 12, 24, 48, 72, 120, and 168 hours post- dose

Population: chemotherapy-naïve cancer patients receiving cisplatin-based chemotherapy 8570 35800 1.66 - N: 161 (35 included in PK analysis) 3 µg/kg [N=6] IV Infused 5630 ng/L 56.4 h (SD 7.91 L/kg ng∙h/L (SD ng∙h/L (SD mL/min/kg - Mean age: 60 years (range: 23-79 years) over 30 seconds (SD 5480) f 5.8) (SD 2.53) 4220) 20900) (SD 0.59) - M:F=129:32 - Mean weight: 74 kg (range: 39-132 kg) - Ethnicity: White: 81%; Black: 13%; Hispanic: 4%; Asian: 1%; Other: 1% - Country study was conducted: United States

155

First author Palonosetron Pharmacokinetic Parametersa (year of Study Design, Population Palonosetron Dosing C AUC AUC t CL V publication) max 0-t 0-∞ 1/2 T d,ss 10 µg/kg Stoltz Study design: open-label pharmacokinetic study 3 (2004) 31 mL/min/kg 7.66 L/kg Blood Sampling Times: pre-dose, and 5, 15, and 30 56600 ng- (SD 0.53) (SD 2.87) 3940 ng/L 28.8 h (SD minutes and 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, Male NR Eq∙h/L (SD (SD 560) 5.5) and 144 hours post- dose 9300) 258 659 L mL/min (SD 247)g Population: healthy [14C]- (SD 46)g - N: 6 palonosetron 2.33 - Mean age: 35 years (range: 21-44 years) 10 µg/kg IV mL/min/kg 9.02 L/kg - M:F=3:3 once (infusion 73300 ng- (SD 0.48) (SD 2.33) 2330 ng/L 46.0 h (SD - Mean weight: males, 86 kg (range: NR); rate NR) Female NR Eq∙h/L (SD (SD 380) 15.9) females, 64kg (range: NR) 13400) 149 577 L - Ethnicity: Caucasian: 83% mL/min (SD 149)g

- Country study was conducted: United States (SD 31)g 65000 ng- 2.67 3130 ng/L 37.4 h (SD 8.34 L/kg Combined NR Eq∙h/L (SD mL/h/kg (SD 980) 14.2) (SD 2.45) 13800) (SD 0.58)

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First author Palonosetron Pharmacokinetic Parametersa (year of Study Design, Population Palonosetron Dosing C AUC AUC t CL V publication) max 0-t 0-∞ 1/2 T d,ss Stoltz Study design: pharmacokinetic evaluation of (2004) 31 palonosetron based on 2 phase I, randomized, double-blind, placebo controlled, dose-ascending studies - Study 1: palonosetron dose infused over 5 minutes o 9 dose levels: 0.3, 1, 3, 10, 20, 30, 45, 60 and 90 µg/kg IV once - Study 2: palonosetron dose given as IV bolus infused over 30 seconds o 4 dose levels: 3, 10, 30 and 90 2.66 µg/kg IV once mL/min/kg 7.83 L/kg

65700 (SD 0.805) (SD 1.81) Study 1 10 µg/kg [N=12] IV, infused 3530 ng/L 35.0 h (SD NR ng∙h/L (SD Blood Sampling Times: pre-dose, and 5, 10, 15, 30, over 5 minutes (SD 1440) 8.77) 14500) 239 705 L and 45 minutes and 1, 1.5, 2, 4, 6, 8, 12, 24, 36, mL/min (SD 163)g and 48 hours post- dose and at 72 and 168 hours (SD 72)g post-dose in subjects receiving doses ≥10µg/kg

Population: healthy males - N: 80 (60 included in PK analysis) - Mean age: o 10 µg/kg: 26 years (range: 18-44 years) - M:F=80:0 - Mean weight: o 10 µg/kg: 90 kg (range: 76-104 kg) - Ethnicity: White: 90%; Asian: 4%; Black: 6% - Country study was conducted: United States

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First author Palonosetron Pharmacokinetic Parametersa (year of Study Design, Population Palonosetron Dosing C AUC AUC t CL V publication) max 0-t 0-∞ 1/2 T d,ss Study 2

Blood Sampling Times: pre-dose, and 1, 5, 15, and 30 minutes and 1, 2, 4, 6, 12, 24, 48, 72, 120, 144 and 168 hours post- dose 3.37 mL/min/kg 9.85 L/kg Population: healthy males 51200 (SD 0.747) (SD 1.90) 10 µg/kg [N=6] IV, infused 7790 ng/L 34.1 h (SD - N: 32 (24 included in PK analysis) NR ng∙h/L (SD over 30 seconds (SD 3310) 3.75) - Mean age: 9440) 212 621 L o 10 µg/kg: 21 years (range: 20-21 years) mL/min (SD 120)g - M:F=32:0 (SD 47)g - Mean weight: o 10 µg/kg: 63 kg (range: 55-73 kg) - Ethnicity: Asian: 100% - Country study was conducted: Japan Eisenberg Study design: randomized, double-blind, (2004) 32 multicenter, parallel-design - 5 dose levels: 1, 3, 10, 30 and 90 µg/kg IV once

Blood Sampling Times: pre-dose, and 15 and 30 minutes and 1, 2, 3, 4, 5, 6, 12, 24, 48, 72, 120, and 168 hours post- dose 13000 26600 81800 2.23 10 µg/kg [N=5] IV Infused 49.8 h (SD 9.56 L/kg Population: chemotherapy-naïve cancer patients ng/L (SD ng∙h/L (SD ng∙h/L (SD mL/min/kg over 30 seconds 14.4) (SD 4.21) receiving cisplatin-based chemotherapy 20100) 5990)f 23900) (SD 0.83) - N: 161 (35 included in PK analysis) - Mean age: 60 years (range: 23-79 years) - M:F=129:32 - Mean weight: 74 kg (range: 39-132 kg) - Ethnicity: White: 81%; Black: 13%; Hispanic: 4%; Asian: 1%; Other: 1% - Country study was conducted: United States

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First author Palonosetron Pharmacokinetic Parametersa (year of Study Design, Population Palonosetron Dosing C AUC AUC t CL V publication) max 0-t 0-∞ 1/2 T d,ss 20 µg/kg Stoltz Study design: pharmacokinetic evaluation of (2004) 31 palonosetron based on 2 phase I, randomized, double-blind, placebo controlled, dose-ascending studies - Study 1: palonosetron dose infused over 5 minutes o 9 dose levels: 0.3, 1, 3, 10, 20, 30, 45, 60 and 90 µg/kg IV once - Study 2: palonosetron dose given as IV bolus infused over 30 seconds o 4 dose levels: 3, 10, 30 and 90 2.36 µg/kg IV once mL/min/kg 7.27 L/kg

20 µg/kg [N=6] IV, infused 153000 (SD 0.766) (SD 1.19) Study 1 5710 ng/L 37.0 h (SD over 5 minutes NR ng∙h/L (SD Blood Sampling Times: pre-dose, and 5, 10, 15, 30, (SD 2930) 6.15) 44100) 194 669 L and 45 minutes and 1, 1.5, 2, 4, 6, 8, 12, 24, 36, mL/min (SD 98)g and 48 hours post- dose and at 72 and 168 hours (SD 63)g post-dose in subjects receiving doses ≥10µg/kg

Population: healthy males - N: 80 (60 included in PK analysis) - Mean age: o 20 µg/kg: 22 years (19-25 years) - M:F=80:0 - Mean weight: o 20 µg/kg: 82 kg (range: 77-96 kg) - Ethnicity: White: 90%; Asian: 4%; Black: 6% - Country study was conducted: United States

159

11500 150000 (SD 1.81) (SD 5.52) Study 1 30 µg/kg [N=6] IV, infused 37.8 h (SD ng/L (SD NR ng∙h/L (SD Blood Sampling Times: pre-dose, and 5, 10, 15, 30, over 5 minutes 6.60) 8710) 56100) 269 869 L and 45 minutes and 1, 1.5, 2, 4, 6, 8, 12, 24, 36, mL/min (SD 381)g and 48 hours post- dose and at 72 and 168 hours (SD 125)g post-dose in subjects receiving doses ≥10µg/kg

Population: healthy males - N: 80 (60 included in PK analysis) - Mean age: o 30 µg/kg: 25 years (range: 18-31 years) - M:F=80:0 - Mean weight: o 30 µg/kg: 69 kg (range: 65-80 kg) - Ethnicity: White: 90%; Asian: 4%; Black: 6% - Country study was conducted: United States

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First author Palonosetron Pharmacokinetic Parametersa (year of Study Design, Population Palonosetron Dosing C AUC AUC t CL V publication) max 0-t 0-∞ 1/2 T d,ss Study 1 Blood Sampling Times: pre-dose, and 1, 5, 15, and 30 minutes and 1, 2, 4, 6, 12, 24, 48, 72, 120, 144 and 168 hours post- dose 2.58

mL/min/kg 6.96 L/kg Population: healthy males 23300 208000 (SD 0.667) (SD 1.75) - N: 32 (24 included in PK analysis) 30 µg/kg [N=6] IV, infused 31.3 h (SD ng/L (SD NR ng∙h/L (SD - Mean age: over 30 seconds 3.55) 32300) 68300) 170 459 L o 30 µg/kg: 24 years (range: 20-31 years) mL/min (SD 116)g - M:F=32:0 (SD 44)g - Mean weight: o 30 µg/kg: 66 kg (range: 62-79 kg) - Ethnicity: Asian: 100% - Country study was conducted: Japan Eisenberg Study design: randomized, double-blind, (2004) 32 multicenter, parallel-design - 5 dose levels: 1, 3, 10, 30 and 90 µg/kg IV once

Blood Sampling Times: pre-dose, and 15 and 30 minutes and 1, 2, 3, 4, 5, 6, 12, 24, 48, 72, 120, and 168 hours post- dose 35700 82600 348000 2.13 30 µg/kg [N=8] IV Infused 86.4 h (SD 9.18 L/kg ng/L (SD ng∙h/L (SD ng∙h/L (SD mL/min/kg Population: chemotherapy-naïve cancer patients over 30 seconds 121) (SD 4.61) 37000) 25500)f 295000) (SD 1.21) receiving cisplatin-based chemotherapy - N: 161 (35 included in PK analysis) - Mean age: 60 years (range: 23-79 years) - M:F=129:32 - Mean weight: 74 kg (range: 39-132 kg) - Ethnicity: White: 81%; Black: 13%; Hispanic: 4%; Asian: 1%; Other: 1% - Country study was conducted: United States

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First author Palonosetron Pharmacokinetic Parametersa (year of Study Design, Population Palonosetron Dosing C AUC AUC t CL V publication) max 0-t 0-∞ 1/2 T d,ss 45 µg/kg Stoltz Study design: pharmacokinetic evaluation of (2004) 31 palonosetron based on 2 phase I, randomized, double-blind, placebo controlled, dose-ascending studies - Study 1: palonosetron dose infused over 5 minutes o 9 dose levels: 0.3, 1, 3, 10, 20, 30, 45, 60 and 90 µg/kg IV once - Study 2: palonosetron dose given as IV bolus infused over 30 seconds o 4 dose levels: 3, 10, 30 and 90 µg/kg IV once 2.39

mL/min/kg 8.23 L/kg

26000 348000 (SD 0.717) (SD 1.90) Study 2 45 µg/kg [N=6] IV, infused 41.2 h (SD ng/L (SD NR ng∙h/L (SD Blood Sampling Times: pre-dose, and 5, 10, 15, 30, over 5 minutes 7.33) 23700) 137000) 186 642 L and 45 minutes and 1, 1.5, 2, 4, 6, 8, 12, 24, 36, mL/min (SD 148)g and 48 hours post- dose and at 72 and 168 hours (SD 56)g post-dose in subjects receiving doses ≥10µg/kg

Population: healthy males - N: 80 (60 included in PK analysis) - Mean age: o 45 µg/kg: 24 years (range: 21-34 years) - M:F=80:0 - Mean weight: o 45 µg/kg: 78 kg (range: 69-89 kg) - Ethnicity: White: 90%; Asian: 4%; Black: 6% (5/80) - Country study was conducted: United States

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First author Palonosetron Pharmacokinetic Parametersa (year of Study Design, Population Palonosetron Dosing C AUC AUC t CL V publication) max 0-t 0-∞ 1/2 T d,ss 60 µg/kg Stoltz Study design: pharmacokinetic evaluation of (2004) 31 palonosetron based on 2 phase I, randomized, double-blind, placebo controlled, dose-ascending studies - Study 1: palonosetron dose infused over 5 minutes o 9 dose levels: 0.3, 1, 3, 10, 20, 30, 45, 60 and 90 µg/kg IV once - Study 2: palonosetron dose given as IV bolus infused over 30 seconds o 4 dose levels: 3, 10, 30 and 90 2.78 µg/kg IV once mL/min/kg 9.78 L/kg

60 µg/kg [N=6] IV, infused 17100 370000 (SD 0.488) (SD 1.17) Study 2 41.8 h (SD over 5 minutes ng/L (SD NR ng∙h/L (SD Blood Sampling Times: pre-dose, and 5, 10, 15, 30, 9.55) 4370) 70100) 206 724 L and 45 minutes and 1, 1.5, 2, 4, 6, 8, 12, 24, 36, mL/min (SD 87)g and 48 hours post- dose and at 72 and 168 hours (SD 36)g post-dose in subjects receiving doses ≥10µg/kg

Population: healthy males - N: 80 (60 included in PK analysis) - Mean age: o 60 µg/kg: 24 years (range: 19-40 years) - M:F=80:0 - Mean weight: o 60 µg/kg: 74 kg (range: 68-86 kg) - Ethnicity: White: 90%; Asian: 4%; Black: 6% - Country study was conducted: United States

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First author Palonosetron Pharmacokinetic Parametersa (year of Study Design, Population Palonosetron Dosing C AUC AUC t CL V publication) max 0-t 0-∞ 1/2 T d,ss 90 µg/kg Stoltz Study design: pharmacokinetic evaluation of (2004) 31 palonosetron based on 2 phase I, randomized, double-blind, placebo controlled, dose-ascending studies - Study 1: palonosetron dose infused over 5 minutes o 9 dose levels: 0.3, 1, 3, 10, 20, 30, 45, 60 and 90 µg/kg IV once - Study 2: palonosetron dose given as IV bolus infused over 30 seconds o 4 dose levels: 3, 10, 30 and 90 2.17 µg/kg IV once mL/min/kg 7.50 L/kg

23900 750000 (SD 0.578) (SD 2.25) Study 1 90 µg/kg [N=6] IV, infused 40.2 h (SD ng/L (SD NR ng∙h/L (SD Blood Sampling Times: pre-dose, and 5, 10, 15, 30, over 5 minutes 6.63) 3870) 271000) 182 630 L and 45 minutes and 1, 1.5, 2, 4, 6, 8, 12, 24, 36, mL/min (SD 189)g and 48 hours post- dose and at 72 and 168 hours (SD 49)g post-dose in subjects receiving doses ≥10µg/kg

Population: healthy males - N: 80 (60 included in PK analysis) - Mean age: o 90 µg/kg: 27 years (range: 19-44 years) - M:F=80:0 - Mean weight: o 90 µg/kg: 84 kg (range: 76-101 kg) - Ethnicity: White: 90%; Asian: 4%; Black: 6% - Country study was conducted: United States

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First author Palonosetron Pharmacokinetic Parametersa (year of Study Design, Population Palonosetron Dosing C AUC AUC t CL V publication) max 0-t 0-∞ 1/2 T d,ss Study 2

Blood Sampling Times: pre-dose, and 1, 5, 15, and 30 minutes and 1, 2, 4, 6, 12, 24, 48, 72, 120, 144 2.78 and 168 hours post- dose mL/min/kg 8.70 L/kg (SD 0.549) Population: healthy males 52600 561000 (SD 1.24) 90 µg/kg [N=6] IV, infused 36.8 h (SD - N: 32 (24 included in PK analysis) ng/L (SD NR ng∙h/L (SD over 30 seconds 4.72) 178 - Mean age: 36700) 129000) 557 L mL/min o 90 µg/kg: 23 years (range: 20-26 years) (SD 79)g (SD 35)g - M:F=32:0

- Mean weight: o 90 µg/kg: 64 kg (range: 57-71 kg) - Ethnicity: Asian: 100% - Country study was conducted: Japan Eisenberg Study design: randomized, double-blind, (2004) multicenter, parallel-design - 5 dose levels: 1, 3, 10, 30 and 90 µg/kg IV once

Blood Sampling Times: pre-dose, and 15 and 30 minutes and 1, 2, 3, 4, 5, 6, 12, 24, 48, 72, 120, and 168 hours post- dose 336000 310000 957000 1.90 43.7 h (SD 6.83 L/kg 90 µg/kg [N=12] IV ng/L (SD ng∙h/L (SD ng∙h/L (SD mL/min/kg Population: chemotherapy-naïve cancer patients 12.2) (SD 2.67) 940000) 155000)f 450000) (SD 0.82) receiving cisplatin-based chemotherapy - N: 161 (35 included in PK analysis) - Mean age: 60 years (range: 23-79 years) - M:F=129:32 - Mean weight: 74 kg (range: 39-132 kg) - Ethnicity: White: 81%; Black: 13%; Hispanic: 4%; Asian: 1%; Other: 1% - Country study was conducted: United States

IV, intravenous; SC, subcutaneous; NR, not reported; M, male; F, female; CV, coefficient of variation; SD, standard deviation; Cmax, maximum concentration; AUC0-t, area-under-the concentration time curve up to last measurable; AUC0-∞, area-under-the concentration time curve up to time infinity; t1/2, half-life; CLT, total body clearance; Vd,ss, volume of distribution at steady-state a b c d All parameters are reported as arithmetic mean unless otherwise stated; Geometric mean and standard deviation; Volume of distribution calculated from elimination phase (Vdz); One subject discontinued from the study before the administration of NEPA and is therefore excluded from the pharmacokinetic analysis; eSampling time interval was 0-2.5 hours after each palonosetron dose f AUC0-24h gPanel-calculated based on subject weight reported by study authors 165

E. Pediatric Palonosetron Dosing and Pharmacokinetics

Current pediatric dose (<17 years of age) licensed by: FDA and EMA: 0.02 mcg/kg IV once (max: 1.5 mg/dose); Health Canada: No pediatric recommendation Current adult dose licensed by: FDA and EMA (≥17 years of age): 0.25 mg IV once; Health Canada: 0.25 mg IV once or 0.5 mg PO once

Supplementary Table A13. Palonosetron pharmacokinetic information provided in European Medicine’s Agency palonosetron approval document Pediatric Cancer Patientsa Adult Cancer Patientsb 0.02 mg/kg 0.02 mg /kg 0.02 mg /kg 0.02 mg /kg PK Parameter 0.003 mg /kg 0.01 mg/kg <2 years 2 to <6 years 6 to <12 years 12 to <17 years N=3 N=5 N=7 N=10 N=6 N=5

AUC0-inf, h·µg/L 69.0 (49.5) 103.5 (40.4) 98.7 (47.7) 124.5 (19.1) 35.8 (20.9) 81.8 (23.9) t½, hours 24.0 28 23.3 30.5 56.4 (5.81) 49.8 (14.4) N=6 N=14 N=13 N=19 N=6 N=5 Clearancec, L/h/kg 0.31 (34.7) 0.23 (51.3) 0.19 (46.8) 0.16 (27.8) 0.10 (0.04) 0.13 (0.05) Volume of distributionc.d, 6.08 (36.5) 5.29 (57.8) 6.26 (40.0) 6.20 (29.0) 7.91 (2.53) 9.56 (4.21) L/kg a PK parameters expressed as Geometric Mean (CV) except for t½ which is median. bPK parameters expressed as Arithmetic mean (SD). cClearance and Volume of distribution in paediatric patients were calculated weight-adjusted from both 10 µg /kg and 20 µg /kg dose groups combined. In adults, different dose levels are indicated in column title. d Vss is reported for paediatric cancer patients, whereas Vz (terminal phase volume) is reported for adult cancer patients. N= number of patients

Supplementary Table A14. Summary of palonosetron dosing from available pediatric data Study Age range HEC or Concomitant Palonosetron Dose Dose Complete Control Rate (years) MEC Corticosteroids for Acute CINV* Tang (2013) 3 5-27 HEC No palonosetron 0.25 mg IV Vomiting: 70% (28/40) once Nausea: 83% (33/40) Kovács (2016) 5 0.2-16.9 HEC + Yes (38/254 palonosetron 10 µg/kg IV 54% (90/166) MEC receiving one- once day chemo palonosetron 20 µg/kg IV 59% (98/165) regimen) once Sepúlveda- 1.7-15 HEC No palonosetron 0.25 mg IV Vomiting: 92% (46/50) Vildósola (2008) 6 once Nadaraja (2011) 7 2-18 MEC No palonosetron 5 µg/kg IV once 84% (116/138 courses) Nausea: 77% (106/138 courses) Patil (2015) 8 2.2-17 HEC + Yes palonosetron 5 µg/kg IV once 70% (56/80) MEC Varrasso (2013) 6-18 MEC No palonosetron 5 µg/kg/dose 91% (40/44) [abstract] 10 (max: 250 mcg/dose) IV once Day 1 if chemotherapy regimen <3 days or on Day 1 and 3 if chemotherapy regimen ≥3 days Ripaldi (2010) 12 1-18 MEC No palonosetron 5µg/kg IV once 68% (32/47) *Please refer to full evidence tables (Supplementary Tables A2-A5) for definitions of complete control. Where vomiting and nausea have been specified, it is complete control of vomiting and nausea, respectively, during the acute phase. 166

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F. External Content Review of Draft Guideline

Supplementary Table A15. Expert content reviewers’ agreement with survey statements Neither Strongly Strongly Average Item Agree agree Disagree Agree disagree Rating* nor disagree The literature search described in the draft report is 60% 20% 0% 20% 0% 4.20 complete (no key studies or guidelines were missed). (3) (1) (0) (1) (0) I agree with the methods used to summarize the 60.0% 40.0% 0% 0% 0% 4.60 evidence included in the draft report. (3) (2) (0) (0) (0) The results of the studies described in the report are 40.0% 40.0% 20% 0% 0% 4.20 interpreted according to my understanding of the data. (2) (2) (1) (0) (0) 60.0% 40.0% 0% 0% 0% The recommendations are clear. 4.60 (3) (2) (0) (0) (0) 40% 60% 0% 0% 0% I agree with the recommendations as stated. 4.40 (2) (3) (0) (0) (0) I would feel comfortable having these recommendations 40% 60% 0% 0% 0% 4.40 applied in my hospital (2) (3) (0) (0) (0) *5-point rating scale where 1=strongly disagree and 5=strongly agree.

Supplementary Table A16. Comments of external content reviewers and panel responses Reviewer Comment CPG Panel Response It may be helpful to include the panel’s The following definition was added to the definition of nausea. Introduction: Nausea is defined as the subjective sensation that one might vomit. Why was the evidence for fosaprepitant not Fosaprepitant was included in the literature reviewed? search update. No studies describing fosaprepitant use met criteria for inclusion in our systematic review. Why was the case report by Smith in 2005 This case report did not meet criteria for included? inclusion in the systematic review and was inadvertently included in the supplementary data summary table. It has been removed. Palonosetron: Supplementary Tables A2-A5 summarize the The studies that I assume included children included studies which evaluated palonosetron in (which is hard to determine in the evidence children. One comparative pediatric trial tables) that reported looking at palonosetron (Sepúlveda-Vildósola et al) observed superior vs ondansetron did not show statistical CIV control in the palonosetron arm. The meta- significance based on the p values and the analysis (Popovic et al) which underpins the meta-analysis reviewed was in adult patients. recommendations for palonosetron monotherapy Although I recognize that children who when dexamethasone cannot be given did include cannot receive dexamethasone and/or pediatric patients although the majority were aprepitant are at risk of failure with single adults. These recommendations are categorized agent ondansetron I do not see robust as weak which will prompt institutions and evidence to suggest a higher benefit of clinicians to consider preferences and values in palonosetron in these children. The their decision to use palonosetron. pharmacokinetic data reported is all adult The available pediatric pharmacokinetic data are

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Reviewer Comment CPG Panel Response data so extrapolating to children although not reported in Supplementary Table A13. ideal is reflected in suggested dosing With respect to the risk of QTc prolongation however difficult to relate to clinical associated with palonosetron, no signal of outcomes both efficacy and what I am increased risk with palonosetron has been concerned with is toxicity especially QTc observed to date. Popovic et al identified 3 RCTs prolongation of palonosetron vs ondansetron which reported mean QTc interval increases after especially in children less than 6 months. treatment with 5-HT3 antagonists and concluded that palonosetron (n=1,213) was significantly safer than other 5-HT3RAs (n=604) in this respect (respective weighted means, 2.45 versus 5.13 ms, p=0.002). With respect to QTc prolongation in children, Kovacs et al obtained 12-lead electrocardiograms at the end of the first study drug administration on day 1 and between days 7 and 10. One of the 230 children who received palonosetron and two of the 164 children who received ondansetron experienced prolonged QTc. The age of these children is unknown.

The report is complete and clear. The No change. recommendations take into account the level of evidence available. There are essentially no gaps in the recommendations. In summary, this was a very thorough review and analysis of the literature. It produced a document that provides sound guidelines in terms of use and dosing for aprepitant and palonosetron for essentially all pediatric patients. It seems this is very thorough summary of No change. the literature and recommendations In the results; I would start with for the Wording of the Results was revised for clarity. update xxxx studies were found. So it becomes more clear how many studies were included first and how many added in the update In the paragraph same page where you say no evidence for use of palonosetron in low or minimal emetogenicity it might be good to add here so many studies did find effect in moderate and high emetogenicity and then the further workout as you have done on next page so just help the reader focus on to the studies described (page 4) In the summary I would add aprepitant not This information was added to the remarks and recommended for children < 6 months and readers are referred to the 2013 guideline where a

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Reviewer Comment CPG Panel Response not in children who receive HEC interacting list of antineoplastic agents which are known or with aprepitant and somewhere in the suspected to interact with aprepitant is presented. supplementary file I would add the list of most used drugs in paediatric oncology that can interact with aprepitant. page 11 I find it striking that there are no This topic has been added to Table 2.4 and its dose finding studies of palonosetron. I find importance has been emphasized in the text. this has to be stressed in the conclusions that among all the evidence gaps this needs to be prioritized especially because of big difference in dose between adults and children.

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G. Health Questions, Summary of Recommendations and Remarks for the Prevention of Acute Chemotherapy-Induced Nausea and Vomiting in Children

Supplementary Table A17. Health questions, summary of recommendations and remarks for the prevention of acute chemotherapy-induced nausea and vomiting in children 1. HIGHLY EMETOGENIC CHEMOTHERAPY What pharmacological interventions provide optimal control of acute chemotherapy-induced nausea and vomiting (CINV) in children receiving highly emetogenic chemotherapy (HEC)? Previous Recommendations (2013) New Recommendations (2016) We recommend that: 1.1. We recommend that children ≥6 months old Children ≥ 12 years old and receiving receiving HEC which is not known or suspected antineoplastic agents of high emetic risk which are to interact with aprepitant receive: not known or suspected to interact with granisetron or ondansetron or palonosetron + aprepitant receive: dexamethasone + aprepitant aprepitant + ondansetron or granisetron + dexamethasone Strong recommendation, Strong recommendation, moderate quality evidence very low quality evidence 1.2. We recommend that children <6 months old Children < 12 years old and receiving receiving HEC receive: antineoplastic agents of high emetic risk receive: granisetron or ondansetron or palonosetron + ondansetron or granisetron + dexamethasone dexamethasone

Strong recommendation, Strong recommendation, moderate quality evidence moderate quality evidence

Children ≥ 12 years old and receiving 1.3. We recommend that children ≥6 months antineoplastic agents of high emetic risk which are receiving HEC which is known or suspected to known or suspected to interact with aprepitant interact with aprepitant receive: receive: granisetron or ondansetron or palonosetron + ondansetron or granisetron + dexamethasone dexamethasone

Strong recommendation, Strong recommendation, moderate quality evidence moderate quality evidence Remarks: In developing these recommendations, the trial demonstrating increased complete chemotherapy-induced vomiting (CIV) control rates in children given aprepitant in combination with a 5- 1 HT3 antagonist and dexamethasone was valued highly by the panel. Aprepitant is not recommended for use in children less than 6 months of age because it has not been studied in this age group for the purpose of CINV prophylaxis. Aprepitant, a moderate CYP3A4 inhibitor, continues to be recommended for use in conjunction with chemotherapy which is not known or suspected to interact. A list of antineoplastic agents which are CYP3A4 substrates is included as a supplementary table in the 2013 33 clinical practice guideline. In recommending palonosetron as a possible 5-HT3 antagonist, high value was placed on the meta-analysis which indicated that complete CIV control rates were comparable in 13 adult and pediatric patients receiving different 5-HT3 antagonists in combination with dexamethasone. The findings of non-inferiority between high-dose palonosetron and ondansetron with/without

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Patel et al. 2016. dexamethasone were also considered.5 What pharmacological interventions provide optimal control of acute CINV in children receiving HEC in whom corticosteroids are contraindicated? Previous Recommendations (2013) New Recommendations (2016) We suggest that children receiving highly 1.4. We recommend that children ≥6 months old emetogenic antineoplastic therapy who cannot receiving HEC which is not known or suspected receive corticosteroids receive: to interact with aprepitant and who cannot ondansetron or granisetron + chlorpromazine or receive dexamethasone for CINV prophylaxis nabilone receive: palonosetron + aprepitant

Weak recommendation, Strong recommendation, low quality evidence moderate quality evidence

No recommendation. 1.5. We suggest that children <6 months old receiving HEC who cannot receive dexamethasone for CINV prophylaxis receive: palonosetron

Weak recommendation, moderate quality evidence

No recommendation. 1.6. We suggest that children receiving HEC which is known or suspected to interact with aprepitant and who cannot receive dexamethasone receive: palonosetron

Weak recommendation, moderate quality evidence Remarks: In developing recommendation 1.4, value was placed on the description of improved CIV control in a subset of patients included in a larger randomized controlled trial who received ondansetron plus aprepitant.4 As explained in earlier, aprepitant is not recommended for children <6 months old. In recommending palonosetron as the preferred 5-HT3 antagonist in recommendations 1.4, 1.5 and 1.6, high value was placed on the meta-analysis13 demonstrating increased acute CIV control with palonosetron versus other 5-HT3 antagonists in the absence of dexamethasone. The guideline panel discussed the inclusion of adjunctive antiemetic agents such as those recommended in the 2013 guideline34 (i.e. chlorpromazine or nabilone) for children less than 6 months old, as well as for children of all ages unable to receive both aprepitant and corticosteroids. However, the absence of direct evidence to support the efficacy or safety of these agents in the younger age group or to support their efficacy in combination with a 5-HT3 antagonist in any age group dissuaded the guideline panel from making such a recommendation. Since direct evidence to support the use of palonosetron monotherapy over other agents for patients receiving HEC in children <6 months old is not available, recommendation 1.5 is a weak recommendation. That is, although the majority of individuals would want the suggested intervention, many would not and the decision to implement the recommendation should be based on patient, clinician and institutional values and preferences.35 Recommendation 1.6 is also a weak recommendation since it is supported primarily by evidence in adult patients and the findings of pediatric trials are inconsistent.

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2. MODERATELY EMETOGENIC CHEMOTHERAPY What pharmacological interventions provide optimal control of acute CINV in children receiving moderately emetogenic chemotherapy (MEC)? Previous Recommendations (2013) New Recommendations (2016) We recommend that children receiving 2.1. We recommend that children receiving antineoplastic agents of moderate MEC receive: emetogenicity receive: granisetron or ondansetron or palonosetron + ondansetron or granisetron + dexamethasone dexamethasone

Strong recommendation, Strong recommendation, moderate quality evidence moderate quality evidence

Remarks: The recommendation to include palonosetron among the recommended 5-HT3 antagonists is based on the meta-analysis13 and the included prospective pediatric studies 5, 8 that demonstrate similar

CIV control rates following palonosetron versus other 5-HT3 antagonists combined with dexamethasone in children receiving MEC. Aprepitant is not included in this recommendation as there is no direct, high quality evidence demonstrating the superiority of aprepitant for CINV prophylaxis for children receiving MEC without a contraindication for corticosteroids. While a greater proportion of patients achieved CIV control with aprepitant versus placebo in the randomized controlled trial4 included in the evidence summary, the number of patients who received dexamethasone in this subset of patients is unclear. What pharmacological interventions provide optimal control of acute CINV in children receiving MEC in whom corticosteroids are contraindicated? Previous Recommendations (2013) New Recommendations (2016) We suggest that children receiving moderately 2.2. We suggest that children ≥6 months receiving emetogenic antineoplastic therapy who cannot MEC who cannot receive dexamethasone for receive corticosteroids receive: CINV prophylaxis receive: ondansetron or granisetron + chlorpromazine granisetron or ondansetron or palonosetron + or aprepitant metoclopramide or nabilone Weak recommendation, Weak recommendation, moderate quality evidence low quality evidence

2.3. We suggest that children <6 months receiving No recommendation MEC who cannot receive dexamethasone for

CINV prophylaxis receive:

palonosetron

Weak recommendation, moderate quality evidence

2.4. We suggest that children receiving MEC No recommendation which is known or suspected to interact with aprepitant and who cannot receive dexamethasone receive: palonosetron

Weak recommendation, moderate quality evidence Remarks: The panel developed recommendations 2.2 to 2.4 with the appreciation that children who cannot receive dexamethasone are more vulnerable to breakthrough and refractory CINV. These 172

Patel et al. 2016. recommendations draw on the evidence of efficacy in children receiving HEC. Value was also placed on the large pediatric randomized controlled trials describing CIV control in the subsets of children receiving MEC and ondansetron plus aprepitant4 and palonosetron monotherapy.5 Given the broad range of emetogenicity risk classified as MEC,36 the panel recognizes that clinicians may wish to reserve palonosetron for children who cannot receive dexamethasone who are about to receive chemotherapy with an emetogenicity risk at the higher end of the MEC range. The panel also considered the inclusion of antiemetic agents such as chlorpromazine, metoclopramide and nabilone for use when aprepitant is not an option. However, the lack of direct evidence to support the efficacy and safety of these agents in children <6 months and the absence of high quality evidence describing their efficacy in combination with a 5-HT3 antagonist dissuaded the guideline panel from recommending their use. Recommendations 2.2, 2.3 and 2.4 are weak recommendations because uncertainty exists regarding the extent of the improvement in CIV control that can be achieved with the implementation of these recommendations due to the lack of direct supporting evidence. 3. ANTIEMETIC DOSING What doses of aprepitant and palonosetron are known to be effective in children receiving chemotherapy? Previous Recommendations (2013) New Recommendations (2016) We recommend the following aprepitant dose 3.1. We suggest the following aprepitant for children 12 years of age and older: dose for children ≥6 months: Day 1: 125mg PO x 1; Day 1: 3 mg/kg (max: 125 mg) PO x 1; Days 2 and 3: 80mg PO once daily Days 2 and 3: 2 mg/kg (max: 80mg) PO once daily

Strong recommendation, Weak recommendation, moderate quality evidence moderate quality evidence Remarks: This recommendation places a high value on the dose simulation information discussed within a pediatric randomized control trial4 and on evidence that this dose improves CIV control in children during the first 24 hours after receipt of HEC or MEC. The recommended dose is in agreement with the aprepitant dose approved for pediatric use by the United States’ Food and Drug Administration (FDA) and the European Medicines Agency (EMA).37, 38 Questions, however, remain regarding the optimal aprepitant dose in children receiving multiple day chemotherapy and whether a single aprepitant dose would be sufficient for children receiving single day chemotherapy. As a result of these uncertainties, this is a weak recommendation. Previous Recommendations (2013) New Recommendations (2016) No recommendation. 3.2. We suggest the following palonosetron dose for children: 1 month to <17 years: 0.02 mg/kg IV once (max 1.5 mg/dose) pre- chemotherapy ≥17 years: 0.25 mg IV or 0.5 mg/dose PO once pre-chemotherapy

Weak recommendation, moderate quality evidence

Remarks: This recommendation places value on the results of a large randomized trial demonstrating the non-inferiority of ondansetron and palonosetron 0.02 mg/kg,5 the current pediatric IV palonosetron

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Patel et al. 2016. dose licensed by the FDA and EMA and the current adult oral palonosetron dose licensed by Health Canada.37, 39 However, while the 0.02 mg/kg dose is safe and effective, it may be unnecessarily high. Since other pediatric studies have demonstrated significant CIV control in patients receiving palonosetron 0.005 mg/kg and 0.01 mg/kg,6, 8, 10, 12, 40 it is unclear if palonosetron 0.02 mg/kg is required to achieve optimal acute CIV control in children or if a lower dose could achieve comparable outcomes. In addition, optimal palonosetron dosing in children receiving multiple day chemotherapy is not known. This is a weak recommendation because the panel is not certain that a palonosetron dose of 0.02 mg/kg is warranted for MEC and HEC.

H. References

1. Bakhshi S, Batra A, Biswas B, Dhawan D, Paul R, Sreenivas V. Aprepitant as an add-on therapy in children receiving highly emetogenic chemotherapy: a randomized, double-blind, placebo-controlled trial. Support Care Cancer. 2015;23(11):3229-37.

2. Long JB, Leslie JB, Hentz JG, Magrina JF. Prevention of postoperative nausea and vomiting in elective hysterectomy: A prospective, randomized, placebo controlled outcomes trial of aprepitant nk-1-receptor antagonist. Female Pelvic Medicine and Reconstructive Surgery. 2013;19:S23.

3. Tang L, Lin F, Yao Y. Efficacy of palonosetron hydrochloride injection in preventing gastrointestinal reactions caused by high-dose chemotherapy in osteosarcoma patients. [Chinese]. Chinese Journal of Clinical Oncology. 2013;40(3):168-70+77.

5. Kovacs G, Wachtel AE, Basharova EV, Spinelli T, Nicolas P, Kabickova E. Palonosetron versus ondansetron for prevention of chemotherapy-induced nausea and vomiting in paediatric patients with cancer receiving moderately or highly emetogenic chemotherapy: a randomised, phase 3, double-blind, double-dummy, non-inferiority study. Lancet Oncology. 2016;17(3):332- 44.

6. Sepulveda-Vildosola AC, Betanzos-Cabrera Y, Lastiri GG, Rivera-Marquez H, Villasis- Keever MA, Del Angel VW, et al. Palonosetron hydrochloride is an effective and safe option to prevent chemotherapy-induced nausea and vomiting in children. Arch Med Res. 2008;39(6):601- 6.

7. Nadaraja S, Rosthoej S, Wehner PS, Thomassen H, Schroeder H. Palonosetron in the prevention of chemotherapy-induced nausea and vomiting in children with acute lymphoblastic leukemia treated with high dose methotrexate. Support Care Cancer. 2011;1):S131-S2.

8. Patil V, Prasada H, Prasad K, Shenoy UV. Comparison of antiemetic efficacy and safety of palonosetron vs ondansetron in the prevention of chemotherapy-induced nausea and vomiting in children. J. 2015;13(6):209-13.

174

Patel et al. 2016.

9. Bodge M, Shillingburg A, Paul S, Biondo L. Safety and efficacy of aprepitant for chemotherapy-induced nausea and vomiting in pediatric patients: a prospective, observational study. Pediatric Blood & Cancer. 2014;61(6):1111-3.

10. Varrasso G, De Grazia A, Mollace MG, Megaro G, Paiano M, Suraci S. Antiemetic efficacy of palonosetron in children receiving moderately emetogenic chemotherapy: Preliminary results. Pediatric Blood and Cancer. 2013;60:174.

11. Bauters TG, Verlooy J, Robays H, Benoit Y, Laureys G. Emesis control by aprepitant in children and adolescents with chemotherapy. Int J Clin Pharm. 2013;35(6):1021-4.

12. Ripaldi M, Parasole R, De Simone G, D'Amico MR, Migliorati R, Zanotta G, et al. Palonosetron to prevent nausea and vomiting in children undergoing BMT: efficacy and safety. Bone Marrow Transplantation. 2010;45(11):1663-4.

13. Popovic M, Warr DG, DeAngelis C, Tsao M, Chan KK, Poon M, et al. Efficacy and safety of palonosetron for the prophylaxis of chemotherapy-induced nausea and vomiting (CINV): a systematic review and meta-analysis of randomized controlled trials. Support Care Cancer. 2014;22(6):1685-97.

14. Maemondo M, Masuda N, Sekine I, Kubota K, Segawa Y, Shibuya M, et al. A phase II study of palonosetron combined with dexamethasone to prevent nausea and vomiting induced by highly emetogenic chemotherapy. Ann Oncol. 2009;20(11):1860-6.

15. Zhang W, Feng F, Le W, Wang H, Zhu L. Sensitive and selective LC-MS-MS assay for the quantification of palonosetron in human plasma and its application to a pharmacokinetic study. Chromatographia. 2008;68(3-4):193-9.

16. Yang S, Qin F, Wang D, Li N, Li F, Xiong Z. Determination of palonosetron in human plasma by ultra performance liquid chromatography-tandem mass spectrometry and its application to a pharmacokinetic study. Journal of Pharmaceutical & Biomedical Analysis. 2012;57:13-8.

17. Shah AK, Hunt TL, Gallagher SC, Cullen MT, Jr. Pharmacokinetics of palonosetron in combination with aprepitant in healthy volunteers. Curr Med Res Opin. 2005;21(4):595-601.

18. Hunt TL, Gallagher SC, Cullen MT, Jr., Shah AK. Evaluation of safety and pharmacokinetics of consecutive multiple-day dosing of palonosetron in healthy subjects. Journal of Clinical Pharmacology. 2005;45(5):589-96.

19. Shah A, DeGroot T, Apseloff G. Pharmacokinetic evaluation and safety profile of a 15- minute versus 30-second infusion of palonosetron in healthy subjects. Journal of Clinical Pharmacology. 2006;46(10):1139-45.

20. Ding L, Chen Y, Yang L, Wen A. Determination of palonosetron in human plasma by liquid chromatography-electrospray ionization-mass spectrometry. Journal of Pharmaceutical & Biomedical Analysis. 2007;44(2):575-80.

175

Patel et al. 2016.

21. Einhorn LH, Brames MJ, Dreicer R, Nichols CR, Cullen MT, Jr., Bubalo J. Palonosetron plus dexamethasone for prevention of chemotherapy-induced nausea and vomiting in patients receiving multiple-day cisplatin chemotherapy for germ cell cancer. Support Care Cancer. 2007;15(11):1293-300.

22. Dai YY, Liu P, Chen Z, Tang ZQ, Feng FY. Pharmacokinetic properties of palonosetron, a 5-hydroxytryptamine-3 receptor antagonist, in Chinese healthy subjects. [Chinese]. Chinese Journal of New Drugs. 2009;18(10):910-3.

23. Li P, Ma P, Wang Y, Tong W, Wang J, Wu C, et al. Liquid chromatography-electrospray quadrupole linear ion trap mass spectrometry method for the quantitation of palonosetron in human plasma and urine: Application to a pharmacokinetic study. J Chromatogr B Analyt Technol Biomed Life Sci. 2012;895-896:10-6.

24. Sun J, Li Z, Zhang Y, Yang W, Tang S, Hu J. Study on pharmacokinetics of palonosetron hydrochloride in healthy volunteers. [Chinese]. Pharmaceutical Care and Research. 2012;12(6):465-8.

25. Shi XL, Shao FX, Song M, Hang TJ, Yang L, Wen AD, et al. Pharmacokinetics and bioavailability of palonosetron hydrochloride capsules in healthy volunteers. [Chinese]. Chinese Journal of New Drugs. 2013;22(6):681-5.

26. Sadaba B, del Barrio A, Campanero MA, Azanza JR, Gomez-Guiu A, Lopez-Picazo JM, et al. Randomized pharmacokinetic study comparing subcutaneous and intravenous palonosetron in cancer patients treated with platinum based chemotherapy. PLoS ONE [Electronic Resource]. 2014;9(2):e89747.

27. Calcagnile S, Lanzarotti C, Rossi G, Henriksson A, Kammerer KP, Timmer W. Effect of netupitant, a highly selective NK1 receptor antagonist, on the pharmacokinetics of palonosetron and impact of the fixed dose combination of netupitant and palonosetron when coadministered with ketoconazole, rifampicin, and oral contraceptives. Support Care Cancer. 2013;21(10):2879- 87.

28. Spinelli T, Moresino C, Baumann S, Timmer W, Schultz A. Effects of combined netupitant and palonosetron (NEPA), a cancer supportive care antiemetic, on the ECG of healthy subjects: an ICH E14 thorough QT trial. Springerplus. 2014;3:389.

29. Calcagnile S, Lanzarotti C, Gutacker M, Jakob-Rodamer V, Peter Kammerer K, Timmer W. Evaluation of the effect of food and age on the pharmacokinetics of oral netupitant and palonosetron in healthy subjects: A randomized, open-label, crossover phase 1 study. Clin Pharm Drug Dev. 2015;4(5):377-86.

30. Ikari Y, Ogata K, Nakashima Y, Sato E, Masaki M, Katsuya H, et al. Safety and pharmacokinetic evaluation of repeated intravenous administration of palonosetron 0.75 mg in patients receiving highly or moderately emetogenic chemotherapy. Support Care Cancer. 2014;22(7):1959-64.

176

Patel et al. 2016.

31. Stoltz R, Parisi S, Shah A, Macciocchi A. Pharmacokinetics, metabolism and excretion of intravenous [l4C]-palonosetron in healthy human volunteers. Biopharm Drug Dispos. 2004;25(8):329-37.

32. Eisenberg P, MacKintosh FR, Ritch P, Cornett PA, Macciocchi A. Efficacy, safety and pharmacokinetics of palonosetron in patients receiving highly emetogenic cisplatin-based chemotherapy: a dose-ranging clinical study. Ann Oncol. 2004;15(2):330-7.

33. Dupuis LL, Boodhan S, Sung L, Portwine C, Hain R, McCarthy P, et al. Guideline for the classification of the acute emetogenic potential of antineoplastic medication in pediatric cancer patients. Pediatr Blood Cancer. 2011;57(2):191-8.

34. Dupuis LL, Boodhan S, Holdsworth M, Robinson PD, Hain R, Portwine C, et al. Guideline for the prevention of acute nausea and vomiting due to antineoplastic medication in pediatric cancer patients. Pediatr Blood Cancer. 2013;60(7):1073-82.

35. Andrews J, Schünemannb H, Oxmand A, Pottiee K, Meerpohl J, Coelloh P, et al. GRADE guidelines: 15. Going from evidence to recommendation—determinants of a recommendation's direction and strength. Journal of Clinical Epidemiology. 2013;66(7):726-35.

36. Dupuis LL, Boodhan S, Sung L, Portwine C, Hain R, McCarthy P, et al. Guideline for the classification of the acute emetogenic potential of antineoplastic medication in pediatric cancer patients. Pediatr Blood Cancer. 2011;57(2):191-8.

37. European Medicines Agency. Emend: EPAR - Product Information [Internet]. London: European Medicines Agency; 2016 April [cited 2016 August 2]. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_- _Product_Information/human/000527/WC500026537.pdf.

38. Merck & Co., Inc. . Emend (aprepitant) Product Monograph [Internet]. Merck Sharp & Dohme Corp.; 2015 August [cited 2015 September 15]. Available from: http://www.merck.com/product/usa/pi_circulars/e/emend/emend_pi.pdf.

39. Helsinn Healthcare SA. Aloxi: Prescribing Information [Internet]. Switzerland; Eisai Inc.; 2015 December [cited 2016 August 2]. Available from: http://www.aloxi.com/docs/pdf/PI.pdf.

40. Nadaraja S, Mamoudou AD, Thomassen H, Wehner PS, Rosthoej S, Schroeder H. Palonosetron for the prevention of nausea and vomiting in children with acute lymphoblastic leukemia treated with high dose methotrexate. Pediatr Blood Cancer. 2012;59(5):870-3.

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Appendix B. Supplemental Material for Aprepitant and Fosaprepitant Drug interactions: a systematic review

A. Literature Search

With the assistance of librarians, a literature search was conducted using the following databases: Ovid MEDLINE(R) + Ovid MEDLINE(R) In Process & Other Non-Indexed Citations, Embase Classic + Embase, Cochrane Central Register of Controlled Trials and Web of Science Core Collection from inception to September 11, 2016. The full search strategy used in MEDLINE is presented in Supplementary Table B1 below. A grey literature search was also conducted on September 17, 2016 to identify any additional articles or abstracts. A list of the sources searched is presented in Supplementary Table B2. Information was sought directly from study authors when it was required to fully evaluate a publication’s eligibility for the systematic review or when further clarification about published results was required.

Supplementary Table B1. Search strategy # Search term 1 aprepitant.mp 2 fosaprepitant.mp 3 Emend.mp 4 Emend iv.mp 5 fosaprepitant dimeglumine.mp 6 (mk869 or mk 869 or mk0869 or "mk 0869" or mk-0869 or mk-869).mp 7 (l754030 or l 754030 or l 754,030 or l754,030 or l-754030 or l-754,030 or "l-754 030").mp 8 (mk0517 or "mk 0517" or mk517 or mk 517 mk-0517 or mk-517).mp 9 (l-758,298 or l758,298 or l758298 or l 758,298 or l725298 or l 758298 or l-785,298 or l785,298 or l785298 or l 785,298 or l785298 or l 785298).mp 10 (ono 7436 or ono7536).mp 11 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 12 exp Drug Interactions/ 13 interact*.tw,kf,mp 14 exp Pharmacokinetics/ 15 (Drug* adj3 kinetic*).tw,kf,mp 16 pharmacokinetic*.tw,kf,mp 17 pk.fs 18 (pharma* adj3 kinetic*).tw,kf,mp 19 adverse effect*.mp 20 adverse event*.mp 21 toxicity*.mp 22 agon* or antagon* or synerg*.mp 23 drug interaction.mp

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# Search term 24 CYP*.mp,tw,kf 25 exp Cytochrome P-450 Enzyme System/ 26 Cytochrome*.mp,tw,kf 27 exp product surveillance, postmarketing/ 28 exp adverse drug reaction reporting systems/ 29 (ae or ag or ai or ct or to or me).fs 30 12 or 13 or 14 or 15 or 16 or 17 or 18 or 19 or 20 or 21 or 22 or 23 or 24 or 25 or 26 or 27 or 28 or 29 31 11 and 30 32 Remove duplicates from 31

Supplementary Table B2. List of grey literature sources searched American Society of Clinical Oncology (ASCO) meeting abstracts ClinicalTrials.gov Google Google Scholar International Clinical Trials Registry Platform of the World Health Organization Multinational Association of Supportive Care in Cancer (MASCC) meeting abstracts

B. Publication Selection, Data Extraction and Quality Assessment Procedures

Publication Selection Procedures

Inclusion and exclusion criteria were defined a priori. Publications were included in the systematic review if they: (1) described changes in pharmacokinetic parameters of a drug given concomitantly with aprepitant or fosaprepitant or described an adverse event ascribed to a drug interaction with aprepitant or fosaprepitant; (2) described these events in humans; (3) reported primary data; and (4) were published in full-text or, for meeting abstracts, were published in 2013 or later. There was no restriction placed on study design or language. Letters to the editor were included if all other criteria were met.

Abstract screening and full text screening were completed independently by two reviewers (PP and LLD). Disagreements at any stage of the selection process were resolved through discussion.

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Data Extraction and Quality Assessment:

Data were extracted by one investigator (PP) and independently verified by a second investigator (LLD).

Randomized and nonrandomized studies were evaluated for their risk of bias and quality using a modified Downs and Black quality assessment tool.1 The power question was modified from the original Downs and Black quality assessment tool: one point was assigned if a study reported their power calculation and no points were assigned if there was no report of how the power calculation was completed. The modified tool consisted of 27 questions and had a maximum achievable score of 28 points. The assessment was done independently by two reviewers (PP and LLD). Discrepancies were resolved through discussion. Each item in the assessment was considered individually without attempting to assign an overall quality rating based on the achieved score. Case reports and case series were not assessed for risk of bias. A narrative synthesis of the results was planned, regardless of the quality of the identified publications.

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C. Study Results Supplementary Table B3. Downs and Black quality assessment for publications evaluating pharmacokinetic drug interactions between aprepitant or fosaprepitant and antineoplastic drugs

Studies (First Author, Year) Vadhan- Hsyu Sarantopoulos Walko Bubalo De Jonge Zhang Kaneta Nygren Imbs Loos Egerer Answer Raj Checklist Term (2015) (2014) (2012) (2012) (2005) (2012) (2014) (2005) (2016) (2007) (2010) Options (2015) Reporting 1. Aim clearly Yes=1 1 1 1 1 1 1 1 1 1 0 1 1 described No=0 2. Outcomes Yes=1 0 1 1 0 0 1 0 1 1 0 1 0 clearly described No=0 3. Patient Yes=1 characteristics 0 1 1 1 1 1 1 1 0 1 1 1 No=0 clearly described 4. Interventions Yes=1 1 1 1 1 1 1 1 1 0 1 1 1 clearly described No=0 5. Principal Yes=2 confounders Partially=1 0 1 1 0 0 1 1 0 0 0 1 1 clearly described No =0 6. Main findings Yes=1 1 1 1 0 1 1 1 1 1 0 1 1 clearly described No=0 7. Random variability for the Yes=1 1 1 1 0 0 1 1 1 1 1 1 1 main outcome No=0 provided 8. Adverse events Yes=1 1 1 0 0 0 1 0 1 0 0 0 0 reported No=0 9. Lost to follow up Yes=1 1 1 1 0 1 1 0 1 0 1 1 1 reported No=0 10. Actual p-value Yes=1 0 0 0 0 0 0 0 0 0 0 0 1 reported No=0 External Validity 11. Sample asked Yes=1 to participate No=0 UTD UTD UTD UTD UTD UTD UTD UTD UTD UTD UTD UTD representative of UTD the population UTD, unable to determine

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Studies (First Author, Year) Vadhan- Hsyu Sarantopoulos Walko Bubalo De Jonge Zhang Kaneta Nygren Imbs Loos Egerer Answer Raj Checklist Term (2015) (2014) (2012) (2012) (2005) (2012) (2014) (2005) (2016) (2007) (2010) Options (2015) 12. Sample agreed Yes=1 to participate No=0 UTD 0 0 0 0 0 1 0 UTD 0 0 0 representative of UTD the population 13. Care received Yes=1 similar to other No=0 0 UTD UTD UTD UTD UTD UTD UTD UTD UTD UTD UTD patients UTD Internal Validity - bias Yes=1 14. Attempt to No=0 0 0 1 1 0 0 0 0 UTD 0 0 1 blind participants UTD Yes=1 15. Attempt to No=0 0 0 1 1 0 0 0 0 UTD 0 0 1 blind assessors UTD 16. Data dredging Yes=1 results stated No=0 UTD 1 1 1 1 1 1 1 UTD 1 1 1 clearly UTD 17. Analysis Yes=1 adjusted for length No=0 UTD 1 1 1 0 1 1 1 UTD 1 1 1 of follow up UTD Yes=1 18. Appropriate No=0 1 1 1 1 1 1 1 1 1 1 1 1 statistics UTD Yes=1 19. Reliable No=0 UTD 1 1 1 1 1 1 1 UTD 1 1 1 compliance UTD Yes=1 20. Accurate No=0 UTD 1 1 1 1 1 1 1 UTD 1 1 1 outcome measures UTD UTD, unable to determine

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Studies (First Author, Year) Vadhan- Hsyu Sarantopoulos Walko Bubalo De Jonge Zhang Kaneta Nygren Imbs Loos Egerer Answer Raj Checklist Term (2015) (2014) (2012) (2012) (2005) (2012) (2014) (2005) (2016) (2007) (2010) Options (2015) Internal Validity - confounding Yes=1 21. Same No=0 1 1 1 1 UTD 1 1 1 1 1 1 1 population UTD 22. Participants Yes=1 recruited at the No=0 1 1 1 1 UTD 1 1 1 1 1 1 1 same time UTD Yes=1 23. Randomized No=0 1 0 1 1 0 1 0 1 1 0 1 1 UTD 24. Adequate Yes=1 allocation No=0 0 0 1 1 0 0 0 0 UTD 0 0 1 concealment UTD 25. Adequate Yes=1 adjustment for No=0 1 1 1 0 0 1 1 1 1 0 1 0 confounders UTD Yes=1 26. Loss of follow No=0 1 1 1 0 1 0 1 1 UTD 1 1 UTD up reported UTD Power Yes=1 27. Power No=0 0 1 1 0 1 1 0 1 0 0 1 0 calculation UTD Total Max: 28 12 19 22 14 10 19 16 19 9 12 19 19 UTD, unable to determine

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Supplementary Table B4. Downs and Black quality assessment for publications evaluating pharmacokinetic drug interactions between aprepitant or fosaprepitant and non-antineoplastic drugs Studies (First Author, Year) Answer McCrea Marbury Nakade Takahashi Blum Majumdar Shadle Majumdar Stoch Fujiwara Shah Maie Ibrahim Ngo Depre Feuring Ball TaBeek Checklist Term Li (2006) Options (2003) (2011) (2008) (2011) (2003) (2003) (2004) (2007) (2011) (2014) (2005) (2014) (2008) (2009) (2005) (2003) (2014) (2013) Reporting 1. Aim clearly Yes=1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 described No=0 2. Outcomes clearly Yes=1 1 1 1 1 1 1 1 1 1 1 1 1 0 1 1 1 1 1 1 described No=0 3. Patient Yes=1 characteristics clearly 1 1 1 1 1 1 1 1 1 1 1 1 0 1 1 1 1 1 1 No=0 described 4. Interventions Yes=1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 clearly described No=0 Yes=2 5. Principal Partially= confounders clearly 1 1 2 1 1 1 1 1 1 1 1 1 0 1 2 1 2 1 1 1 described No =0 6. Main findings Yes=1 1 1 0 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 0 clearly described No=0 7. Random variability Yes=1 for the main outcome 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 No=0 provided 8. Adverse events Yes=1 0 1 0 0 0 1 1 1 1 1 1 1 0 0 0 1 1 1 1 reported No=0 9. Lost to follow up Yes=1 0 1 0 1 1 1 1 1 1 1 1 1 0 1 1 1 1 1 1 reported No=0 10. Actual p-value Yes=1 1 0 0 0 1 0 1 1 0 1 1 1 1 1 0 1 1 1 1 reported No=0 External Validity 11. Sample asked to Yes=1 participate No=0 UTD UTD UTD UTD UTD UTD UTD UTD UTD UTD UTD UTD UTD 1 UTD UTD UTD UTD UTD representative of UTD population 12. Sample agreed to Yes=1 participate No=0 0 0 UTD 0 0 0 0 0 0 0 UTD 0 UTD 1 0 0 0 UTD 0 representative of UTD population 13. Care received Yes=1 similar to other No=0 0 0 0 UTD 0 0 0 0 0 0 1 0 UTD 1 0 0 0 UTD 0 patients UTD Internal Validity - bias Yes=1 14. Attempt to blind No=0 0 0 UTD 0 0 0 0 1 0 1 0 0 0 0 1 1 1 1 1 participants UTD

184

Studies (First Author, Year) Answer McCrea Marbury Nakade Takahashi Blum Majumdar Shadle Majumdar Stoch Fujiwara Shah Maie Ibrahim Ngo Depre Feuring Ball TaBeek Checklist Term Li (2006) Options (2003) (2011) (2008) (2011) (2003) (2003) (2004) (2007) (2011) (2014) (2005) (2014) (2008) (2009) (2005) (2003) (2014) (2013) Yes=1 15. Attempt to blind No=0 0 0 UTD 0 0 0 0 1 0 1 0 0 0 0 1 1 1 1 1 assessors UTD Yes=1 16. Data dredging No=0 1 1 1 1 1 1 1 1 1 1 1 1 UTD 1 1 1 1 1 1 results stated clearly UTD 17. Analysis adjusted Yes=1 for length of follow No=0 1 1 1 1 1 1 1 1 1 1 1 1 UTD 1 1 1 1 1 1 up UTD Yes=1 18. Appropriate No=0 1 1 1 1 1 1 1 1 1 1 1 1 0 1 1 1 1 1 1 statistics UTD Yes=1 19. Reliable No=0 1 1 UTD 1 1 1 1 1 1 1 1 1 UTD 0 1 1 1 1 1 compliance UTD Yes=1 20. Accurate outcome No=0 1 1 1 1 1 1 1 1 1 1 1 1 0 1 1 1 1 1 1 measures UTD Internal Validity - confounding Yes=1 21. Same population No=0 1 1 UTD 1 1 1 1 UTD 1 1 1 1 UTD 1 UTD UTD 1 UTD 1 UTD 22. Participants Yes=1 recruited at the same No=0 1 1 UTD UTD 1 1 1 UTD 1 1 1 1 1 1 UTD UTD 1 1 1 time UTD Yes=1 23. Randomized No=0 1 1 UTD 1 1 1 1 1 1 1 0 1 0 0 1 1 1 1 1 UTD 24. Adequate Yes=1 allocation No=0 0 0 UTD 0 0 0 0 1 0 1 0 0 0 0 1 1 1 1 1 concealment UTD 25. Adequate Yes=1 adjustment for No=0 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 confounders UTD Yes=1 26. Loss of follow up No=0 UTD 1 UTD 1 1 1 1 1 1 1 1 1 UTD 1 1 1 1 1 1 reported UTD Power Yes=1 27. Power calculation No=0 0 0 0 0 0 0 0 1 1 0 0 0 0 0 1 1 1 1 0 UTD Total Max: 28 17 19 12 17 19 19 20 22 20 23 20 20 7 20 21 22 25 23 22 UTD, unable to determine

185

Supplementary Table B5. Downs and Black quality assessment for publications evaluating clinical drug interactions between aprepitant or fosaprepitant and antineoplastic and non-antineoplastic drugs Studies (First Author, Year) Checklist Answer Kameda Lundburg Mogi Fuji Hegerova Howell Ho Stern Chenaf Barthelemi Walsh Jones Gupta Mahe Tsuda Takaki Sato (2014) Mir (2012) Term Options (2014) (2014) (2014) (2015) (2015) (2008) (2008) (2015) (2015) (2015) (2013) (2013) (2016) (2016) (2016) (2016) Reporting 1. Aim clearly Yes=1 0 1 1 0 1 1 1 1 0 0 0 1 1 1 1 1 1 1 described No=0 2. Outcomes Yes=1 clearly 0 1 1 1 1 1 1 0 0 0 0 1 1 1 0 0 1 1 No=0 described 3. Patient characteristics Yes=1 1 1 1 0 1 1 1 1 0 1 0 1 1 1 0 0 1 1 clearly No=0 described 4. Interventions Yes=1 1 1 1 0 1 1 1 0 0 0 0 1 1 1 0 0 0 0 clearly No=0 described 5. Principal Yes=2 confounders Partiall 1 1 1 1 1 1 1 1 0 1 0 1 1 1 0 0 1 1 clearly y=1 described No =0 6. Main Yes=1 findings clearly 1 1 0 1 1 1 1 0 1 0 0 1 1 1 1 1 1 1 No=0 described 7. Random variability for Yes=1 the main 0 0 1 0 1 1 1 1 1 0 0 1 1 1 0 0 0 1 No=0 outcome provided 8. Adverse Yes=1 events 0 1 1 0 0 0 0 0 0 0 0 1 1 0 1 1 1 1 No=0 reported 9. Lost to Yes=1 follow up 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 No=0 reported 10. Actual p- Yes=1 0 1 1 1 1 1 1 1 0 0 0 1 1 1 1 1 1 1 value reported No=0 External Validity 11. Sample asked to Yes=1 participate No=0 UTD 1 1 1 1 1 1 1 1 UTD UTD UTD UTD UTD 1 1 1 1 representative UTD of population

186

13. Care received Yes=1 similar No=0 UTD 1 1 UTD UTD UTD UTD UTD UTD UTD UTD 0 0 UTD UTD UTD UTD UTD to other UTD patients

Internal Validity - bias 14. Attempt to Yes=1 blind No=0 0 0 0 0 0 0 0 0 0 0 0 1 1 0 0 0 0 0 participants UTD Yes=1 15. Attempt to No=0 0 0 0 0 0 0 0 0 0 0 0 1 1 0 0 0 0 0 blind assessors UTD 16. Data Yes=1 dredging No=0 1 1 1 UTD 1 1 1 UTD UTD UTD UTD 1 1 1 1 1 1 1 results stated UTD clearly 17. Analysis Yes=1 adjusted for No=0 1 0 1 UTD 1 UTD 0 UTD UTD UTD UTD 1 1 1 UTD 1 1 1 length of UTD follow up 18. Yes=1 Appropriate No=0 UTD 1 1 UTD 1 1 1 0 UTD UTD UTD 1 1 1 1 UTD UTD 1 statistics UTD Yes=1 19. Reliable No=0 1 0 0 0 0 0 0 0 0 0 UTD 1 0 0 0 0 0 0 compliance UTD 20. Accurate Yes=1 outcome No=0 1 0 1 UTD 0 0 0 UTD UTD UTD UTD 1 1 0 UTD UTD 0 1 measures UTD Internal Validity - confounding Yes=1 21. Same No=0 UTD 1 1 1 1 0 1 1 1 UTD UTD 1 1 1 1 1 1 1 population UTD 22. Yes=1 Participants No=0 1 1 1 1 1 UTD 1 1 1 1 1 1 1 1 1 1 1 1 recruited at UTD

187

Studies (First Author, Year) Checklist Answer Kameda Lundburg Mogi Fuji Hegerova Howell Ho Stern Chenaf Barthelemi Walsh Jones Gupta Mahe Tsuda Takaki Sato (2014) Mir (2012) Term Options (2014) (2014) (2014) (2015) (2015) (2008) (2008) (2015) (2015) (2015) (2013) (2013) (2016) (2016) (2016) (2016) the same time Yes=1 23. No=0 0 0 0 0 0 0 0 0 0 0 0 1 1 0 0 0 0 0 Randomized UTD 24. Adequate Yes=1 allocation No=0 0 0 0 0 0 0 0 0 0 0 0 1 1 0 0 0 0 0 concealment UTD 25. Adequate Yes=1 adjustment for No=0 0 1 1 UTD 0 1 0 0 0 UTD UTD 1 1 1 1 0 1 1 confounders UTD 26. Loss of Yes=1 follow up No=0 1 1 1 1 1 1 0 1 1 UTD UTD 1 0 1 1 1 1 1 reported UTD Power Yes=1 27. Power No=0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 calculation UTD Max: Total 11 18 21 10 17 15 15 11 8 4 2 23 21 16 13 12 16 19 28 UTD, unable to determine

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Supplementary Table B6. Studies evaluating pharmacokinetic drug interactions between aprepitant or fosaprepitant and antineoplastic agents Aprepitant and Interacting First Author Pharmacokinetic Parameters Significance and Study Design, Objective, and Population Drug’s Dose + Concomitant (Year) Comments Medications Without aprepitant With aprepitant Antineoplastic Agents Known to be CYP3A4 Substrates Aprepitant + Bosutinib 2 Hsyu (2015) Study Design: open-label, randomized, single Aprepitant: 125 mg PO once Bosutinib Geometric Mean Cmax: Clinically a [abstract] dose, one cohort, two sequence, two period 94.93 ng/mL 146.0 ng/mL significant ?: Yes

crossover study Bosutinib: 500 mg PO once Bosutinib Geometric Mean AUC0-inf : 2268 ng∙h/mL 4719 ng∙h/mL Funding Source: Objective: To evaluate the effect of a single oral Concomitant Medications: NR Pfizer Inc. Bosutinib Mean t1/2: dose of aprepitant on the pharmacokinetic profile 27.79 h 25.99 h of a single oral dose of bosutinib in healthy Confounding Bosutinib Mean CL: b subjects factors : unable to NR NR determine Population: healthy subjects Bosutinib GMR Cmax with/without aprepitant: - N: 20 (18 subjects completed the study) 1.53 (90% CI: 1.27-1.84) Adverse events - Mean age: NR (range: NR) Bosutinib GMR AUC0-inf with/without aprepitant: associated with - M:F = NR 1.99 (90% CI: 1.67-2.37) aprepitant-drug interaction: none observed/reported Aprepitant + Cabazitaxel

Sarantopoulos Study Design: phase 1, multicenter, open-label, Aprepitant: Day 1: 125 mg PO Cabazitaxel Mean Cmax (±SD): Clinically (2014)3 crossover study once; Days 2 and 3: 80 mg PO 166 ± 95.1 ng/mL 185 ± 143 ng/mL significanta?: Yes once daily Cabazitaxel Mean AUC0-last (±SD): Objective: To assess potential of aprepitant to Funding Source: 2 317 ± 98.2 ng∙h/mL 557 ± 547 ng∙h/mL affect cabazitaxel pharmacokinetics when Cabazitaxel: Day 1: 15 mg/m IV Sanofi administered in combination with cisplatin once (dose reduced to 10 Cabazitaxel Mean t1/2 (±SD): mg/m2 in Cycle 2 for one patient 66.9 ± 31.1 h 87.9 ± 33.6 h Confounding Population: solid malignancy due to febrile neutropenia in Cabazitaxel Mean CL (±SD): factorsb: order not - N: 15 (12 patients for PK analysis, cycle 1) 77.6 ± 49.2 L/h 60.0 ± 12.6 L/h (N=6) randomized

incomplete overlap between groups: 11 Cabazitaxel GMR Cmax with/without aprepitant without aprepitant, 8 with aprepitant) Concomitant Medications: normalized to dose: Adverse events 2 - Median age: 56 years (range: 32-71 Day 1: cisplatin 75 mg/m IV 0.87 (90% CI: 0.52-1.46) associated with

years) once Cabazitaxel GMR AUC0-last with/without aprepitant-drug - M:F = 6:9 aprepitant normalized to dose: interaction: none 1.41 (90% CI: 0.91-2.20) observed/reported

189

Aprepitant and Interacting First Author Pharmacokinetic Parameters Significance and Study Design, Objective, and Population Drug’s Dose + Concomitant (Year) Comments Medications Without aprepitant With aprepitant Aprepitant + Cyclophosphamide (CPA) 4 Walko (2012) Study Design: randomized, double-blind, placebo- Aprepitant: Day 1: 125 mg PO CPA + metabolites Geometric Mean Cmax: Clinically a controlled, crossover study once; Days 2 and 3: 80 mg PO CPA: 31.1 µg/mL CPA: 30.8 µg/mL significant ?: Yes once daily 4-OH: 0.96 µg/mL 4-OH: 0.67 µg/mL Objective: to determine the effects of aprepitant DCE: 0.51 µg/mL DCE: 0.36 µg/mL Funding Source: 2 on CPA, 4-hydroxycyclophosphamide (4-OH) and CPA: Day 1: 600 mg/m IV once CPA + metabolites Geometric Mean AUC0-24h: Merck & Co. Inc., dechloroethylcyclophosphamide (DCE) CPA: 230 µg∙h/mL CPA: 282 µg∙h/mL National Institutes of pharmacokinetics Concomitant Medications: 4-OH: 6.96 µg∙h/mL 4-OH: 6.80 µg∙h/mL Health 2 Day 1: doxorubicin 60 mg/m IV DCE: 9.37 µg∙h/mL DCE: 6.76 µg∙h/mL Population: breast cancer patients once + ondansetron 24 mg PO Confounding CPA Geometric Mean AUC0-inf: b - N: 19 (18 patients for PK analysis) once + lorazepam 1 mg PO q4h 230 µg∙h/mL 317 µg∙h/mL factors : use of - Median age: 55 years (range: 38-77 prn + prochlorperazine 10 mg dexamethasone, CPA Arithmetic Mean CPA t (±SD): years) PO q6h prn 1/2 doxorubicin, and 6.07 h ± 1.93 h 7.29 h ± 1.73 - M:F = 1:18 Day 2 and 3: dexamethasone 8 chemotherapy mg PO once daily + lorazepam 1 CPA Geometric Mean CPA CL: frequency mg PO q4h prn + 4.83 L/h 3.77 L/h inconsistent across prochlorperazine 10 mg PO q6h CPA + metabolites GMR Cmax with/without arms prn aprepitant: CPA: 0.99 (90% CI: 0.92-1.06) Adverse events 4-OH: 0.70 (90% CI: 0.55-0.87) associated with DCE: 0.71 (90% CI: 0.62-0.78) aprepitant-drug CPA GMR + metabolites AUC0-24h with/without interaction: none aprepitant: observed/ reported CPA: 1.23 (90%CI: 1.13-1.33) 4-OH: 0.98 (90%CI: 0.88-1.08) DCE: 0.72 (90%CI: 0.64-0.81)

CPA GMR AUC0-inf with/without aprepitant: 1.28 (90%CI : 1.17-1.40) 5 Bubalo (2012) Study Design: randomized, double-blind, placebo- Aprepitant: Day 1 HSCT CPA Mean Cmax: Clinically a controlled study conditioning: 125 mg PO; Days 2 NR NR significant ?: UTD

to Day 12: 80 mg PO once daily CPA Mean AUC0-48h:

Objective: to assess pharmacokinetics of NR NR, Funding Source: aprepitant in cancer patients undergoing CPA: Days 5 and 6: 60 mg/kg IV once daily Interpatient CV%: 57% Merck & Co. Inc. hematopoietic stem cell transplant (HSCT) and to examine the potential drug-drug interaction AUC between two groups reported to be similar Concomitant Medications: Confounding between aprepitant and CPA CPA Mean t1/2: b Bu/CPA group: Starting Day 1: factors : NR NR Bu PO administered q6h x16 dexamethasone, Population: Adults scheduled for HSCT receiving CPA Mean CL: doses (initial 1 mg/kg, then as phenytoin, either CPA + total body irradiation (CPA/TBI) NR NR

190

(N=17) or busulfan + CPA (Bu/CPA) (N=23) for HSCT per TDM); phenytoin 1000 mg CPA GMR Cmax with/without aprepitant clonazepam, patients conditioning PO x 3 doses completed 4 hours normalized to dose: did not serve as their - N: 40 (22 patients completed CPA PK before first Bu dose, followed NR own controls by 200 mg PO BID until 24 hours study) after final Bu dose or - Mean age: 46 years (range: 19-63 years) Adverse events levetiracetam 500 mg PO BID + - M:F = 28:12 clonazepam 0.5 mg PO BID associated with starting 7 days prior to first Bu aprepitant-drug dose and final dose 11 hours interaction: NR after final Bu dose; CPA GMR AUC0-last with/without aprepitant Mesna, ondansetron, normalized to dose: dexamethasone (dose reduced NR if patient received aprepitant) De Jonge Study Design: prospective pharmacokinetic study Aprepitant: Day -1: 125 mg PO CPA Mean Cmax: Clinically 6 a (2005) with historical control once (2 patients received 80 mg NR NR significant ?: UTD

- G1: patients receiving aprepitant and 4- PO once); Days 1 to 7: 80 mg PO CPA Mean AUC0-last: day course of either cyclophosphamide, once daily NR NR Funding Source: thiotepa and carboplatin (CTC) or tCTC Dutch Cancer Society CPA Mean t1/2: (1/3 dosing of CTC) CTC (n=6): NR NR - G2: 49 patients who had received same Days 1 to 4: Confounding 2 CPA Mean CL: b chemotherapy regimen without CPA: 1500 mg/m /day IV once factors : aprepitant sampled under same daily NR NR dexamethasone, conditions carboplatin IV (dose calculated CPA GMR Cmax with/without aprepitant fluconazole based on modified Calvert normalized to dose: formula, using target AUC of 5 NR Objective: to determine the influence of mg min/mL/day) Adverse events aprepitant on the bioactivation of CPA and the thiotepa: 120 mg/m2/day IV CPA GMR AUC0-last with/without aprepitant associated with normalized to dose:

191

Aprepitant and Interacting First Author Pharmacokinetic Parameters Significance and Study Design, Objective, and Population Drug’s Dose + Concomitant (Year) Comments Medications Without aprepitant With aprepitant metabolism of thiotepa. Findings with respect to q12h NR aprepitant-drug thiotepa are summarized elsewhere in this table. interaction: NR tCTC (n=2): same as CTC except CPA pharmacokinetic model: formation rate of doses reduced by 1/3 Population: breast cancer or germ cell cancer enzyme pool involved in CPA bioactivation 23% -1 - N: 8 Concomitant medications: lower in presence of aprepitant (0.0170h vs. -1 - Median age: NR (range: NR) mesna 500 mg IV 6x/day x36 0.0220h ) - M:F = 1:7 doses; ciprofloxacin PO and - Inhibition of autoinduction resulted in a 7% fluconazole PO (starting 4 days higher CPA exposure and 5% lower exposure prior to chemotherapy); to 4-OH ranitidine; fytomenadion; folic acid; granisetron 1 mg IV BID and dexamethasone 10 mg IV BID on 4 days of chemotherapy, followed by 1 mg granisetron IV BID and dexamethasone 10 mg IV once daily for 2 days after chemotherapy.

Note: dexamethasone doses in patients receiving aprepitant were not decreased Aprepitant + Dinaciclib 7 Zhang (2012) Study Design: randomized, open-label, 2-cycle Aprepitant: Day 1: 125 mg PO Dinaciclib Mean Cmax (CV%): Clinically a crossover study once; Days 2 and 3: 80 mg PO 1210 ng/mL (61) 1170 ng/mL (28) significant ?: No once daily Dinaciclib Mean AUC (CV%): 0-inf Funding Source: Objective: to assess safety and tolerability of 2610 ng∙h/mL (76) 2570 ng∙h/mL (38) dinaciclib administered with or without aprepitant Dinaciclib: 29.6 mg/m2/dose IV Merck & Co. Inc. Dinaciclib Mean t1/2 (CV%): once every 3 weeks 3.06 h (14) 3.29 h (11) Confounding Population: advanced malignancy b factors : - N: 20 (12 patients completed study) Dinaciclib Mean CL (CV%): dexamethasone - Median age: 52 years (range: 35-70 Concomitant Medications: 15.4 L/h/m2 (43) 12.9 L/h/m2 (33) years) Day 1: dexamethasone 12 mg Adverse events - M:F = 8:12 PO once, ondansetron 32 mg IV Dinaciclib GMR Cmax with/without aprepitant: associated with once 1.06 (90% CI: 0.89-1.26) aprepitant-drug Dinaciclib GMR AUC0-inf with/without aprepitant:

192

Aprepitant and Interacting First Author Pharmacokinetic Parameters Significance and Study Design, Objective, and Population Drug’s Dose + Concomitant (Year) Comments Medications Without aprepitant With aprepitant Days 2 to 4: dexamethasone 8 1.11 (90% CI: 0.93-1.32) interaction (with mg PO once daily versus without aprepitant): hyperuricemia grade 3/4: 11% (2/18) vs 0/17 patients; vomiting: 28% (5/18) vs 6% (1/17) (no p- values provided); authors concluded similar safety profile with/without aprepitant overall Aprepitant + Docetaxel 8 Kaneta (2014) Study Design: prospective, open-label, triple cross- Aprepitant: Day 1: 125 mg PO Docetaxel Mean Cmax (±SD): Clinically over study conducted over 3 chemotherapy blocks once NR NR significanta?: UTD

- G1: aprepitant 3 h before docetaxel; Docetaxel Mean AUC0-7h (±SD): 2 docetaxel alone; aprepitant 1h before Docetaxel: Day 1: 60 mg/m IV 2.86 ± 0.64 µM∙h Aprepitant 3 h before: Funding Source: docetaxel once (2.31 µg·h/mL) 3.06 ± 0.63 µM∙h Ministry of Health, - G2: aprepitant 1 h before docetaxel; (2.47 µg·h/mL) Labour and Welfare docetaxel alone; aprepitant 3 h before Concomitant Medications: Aprepitant 1 h before: of Japan, Japanese docetaxel Docetaxel alone group: Day 1: 2.99 ± 0.74 µM∙h Society for the - G3: docetaxel alone; aprepitant 1 h granisetron 3mg IV once + (2.42 µg·h/mL) Promotion of Science before docetaxel; aprepitant 3 h before dexamethasone 12 mg IV once and the Ministry of Docetaxel Mean AUC0-7h normalized to dose docetaxel Docetaxel + aprepitant group: (±SD): Education, Culture, Sports, Science and Day 2 and onward: optional - 5- 0.0253 ± 0.0060 µM∙h Aprepitant 3 h before: Technology Objective: to evaluate the effects of co- HT 3 antagonist or (0.02 µg·h/mL ) 0.0273 ± 0.0071 µM∙h

administration of aprepitant with docetaxel on the dexamethasone; doses not (0.022 µg·h/mL) pharmacokinetics and toxicity of docetaxel dictated by protocol Confounding Aprepitant 1 h before: b factors : AUC 0.0265 ± 0.0077 µM∙h evaluated from 0 to Population: solid tumor (0.021 µg·h/mL) 7h, dexamethasone - N: 20 (16 patients for PK analysis) Docetaxel Mean half-life (±SD): - Median age: 67.5 years (range: 56-76 5.63 ± 3.6 h Aprepitant 3 h before: years) Adverse events 5.00 ± 1.7 h - M:F = 14:2 associated with Aprepitant 1 h before: aprepitant-drug 5.4 ± 4.2h interaction: none observed/reported

193

Docetaxel Arithmetic Mean Ratio AUC0-7h with/without aprepitantc: Aprepitant 3 h before: 1.07 Aprepitant 1 h before: 1.05

Docetaxel Arithmetic Mean AUC0-7hours with/without aprepitant normalized to dosec: Aprepitant 3 h before: 1.08 Aprepitant 1 h before: 1.05 9 Nygren (2005) Study Design: randomized, open-label, two-period, Aprepitant: Day 1: 125 mg PO Docetaxel Geometric Mean Cmax: Clinically a crossover study once; Days 2 and 3: 80 mg PO 3.53 µg/mL 3.37 µg/mL significant ?: No

once daily Docetaxel Geometric Mean AUC0-last: Objective: to investigate the pharmacokinetic 3.26 µg·h/mL 3.17 µg·h/mL Funding Source: NR. interaction between aprepitant and docetaxel and Docetaxel: Day 1: 71-100 mg/m2 Co-investigators are Docetaxel Geometric Mean AUC0-inf: to investigate the tolerability of concomitant IV once Merck & Co. Inc. 3.51 µg·h/mL 3.39 µg·h/mL treatment with aprepitant and docetaxel employees Docetaxel Harmonic Mean t : Concomitant Medications: Days 1/2 Population: solid malignancy 1 and 2: optional - 10.1 h 8.5 h Confounding - N: 11 (10 patients for PK analysis) dexamethasone 8 mg PO BID ± Docetaxel Geometric Mean Plasma CL: factorsb: 23.3 L/h/m2 24.2 L/h/m2 - Median age: NR (range: 50-68 years) 5HT3 antagonist dexamethasone - M:F = 3:7 Docetaxel GMR Cmax with/without aprepitant: 0.95 (90% CI:0.84-1.09), p>0.250 Adverse events

Docetaxel GMR AUC0-last with/without associated with aprepitant: aprepitant-drug 0.97 (90%CI: 0.86-1.10), p>0.250 interaction: none

Docetaxel GMR AUC0-inf with/without aprepitant: observed/ reported 0.96 (90%CI: 0.84-1.10), p>0.250 Aprepitant + Erlotinib 10 Mir (2011) Study Design: case report; trough erlotinib Aprepitant: 80 mg PO once daily Erlotinib Mean Cmax: Clinically [letter to concentrations described with and without starting on Day 0 NR NR significanta?: UTD editor] aprepitant Erlotinib Mean AUC0-last: Erlotinib: 150 mg (route: NR) NR NR Funding Source: Not

Objective: to present erlotinib PK data for patient once daily Erlotinib Mean t1/2: reported. receiving aprepitant and erlotinib NR NR Concomitant Medications: Confounding Erlotinib Mean Plasma CL: b Population: adenocarcinoma levetiracetam 1000 mg daily, NR NR factors : none. - N: 1 prednisone 5 mg daily Erlotinib GMR Cmax with/without aprepitant: - Age: 54 years Adverse events NR - Sex: NR associated with Erlotinib GMR AUC0-last with/without aprepitant:

194

Aprepitant and Interacting First Author Pharmacokinetic Parameters Significance and Study Design, Objective, and Population Drug’s Dose + Concomitant (Year) Comments Medications Without aprepitant With aprepitant NR aprepitant-drug Erlotinib trough concentrations: interaction: none Day 0: 1210 ng/mL Day 7: 2455 mg/mL observed/reported Day 14: 2440 ng/mL DIPS Score: 7

Aprepitant + Ifosfamide

Durand Study Design: case report; PK of ifosfamide and Aprepitant: Day 1: 125 mg PO Ifosfamide Geometric Mean Cmax: Clinically 11 a (2007) metabolites described with and without aprepitant 1h pre-chemotherapy NR NR significant ?: UTD Ifosfamide Geometric Mean AUC : Objective: to report a suspected case of Ifosfamide: Days 1 and 2 and 14 0-last Funding Source: ifosfamide-induced encephalopathy resulting from and 15 every month: 2.5g/m2 IV NR NR none. an aprepitant-ifosfamide drug interaction once Ifosfamide t1/2: 3.6 h 4.45 h Confounding Population: metastatic osteosarcoma Concomitant Medications: Ifosfamide CL: factorsb: none - N: 1 Days 1 and 2 every month: 73.9 mL/min 119.3 mL/min reported 2 - Age: 57 years doxorubicin 30 mg/m IV once; Ifosfamide GMR Cmax with/without aprepitant: - Sex: F Days 14 and 15 every month: NR Adverse events 2 doxorubicin 30 mg/m IV once Ifosfamide GMR AUC0-last with/without associated with 2 and cisplatinum 50 mg/m IV aprepitant: aprepitant-drug once; ondansetron 8 mg IV 1h NR interaction: pre-chemotherapy, Ifosfamide concentrations: encephalopathy: methylprednisolone 60 mg IV Hour 0: 0.1 µg/mL Hour 0: 0.1 µg/mL - Day 1: marked 1h pre-chemotherapy Hour 2: 69.2 µg/mL Hour 2: 58.6 µg/mL sleepiness, Hour 4: 52 µg/mL Hour 4: 36.7 µg/mL dizziness, visual Hour 7: 31.7 µg/mL Hour 7: 22.5 µg/mL and auditive 2- dechloroethyl-ifosfamide concentrations: hallucinations Hour 0: 0.1 µg/mL Hour 0: 0.1 µg/mL lasting 6 hours Hour 2: 3.53 µg/mL Hour 2: 5.89 µg/mL - Day 2: rechallenge (66.7% increase) – same symptoms Hour 4: 5.74 µg/mL Hour 4: 7.95 µg/mL Hour 7:5.59 µg/mL Hour 7: 7.87 µg/mL DIPS Score: 6

195

Aprepitant and Interacting First Author Pharmacokinetic Parameters Significance and Study Design, Objective, and Population Drug’s Dose + Concomitant (Year) Comments Medications Without aprepitant With aprepitant 3 dechloroethyl-ifosfamide concentrations: Hour 0: 0.1 µg/mL Hour 0: 0.1 µg/mL Hour 2: 3.43 µg/mL Hour 2: 4.71 µg/mL (37.3% increase) Hour 4: 6.25 µg/mL Hour 4: 6.61 µg/mL Hour 7: 6.55 µg/mL Hour 7: 7.25 µg/mL 4-hydroxy-isfosfamide concentrations: Hour 0: 0.1 µg/mL Hour 0: 0.1 µg/mL Hour 2: 0.64 µg/mL Hour 2: 0.82 µg/mL Hour 4: 0.47 µg/mL Hour 4: 0.6 µg/mL Hour 7: 0.31 µg/mL Hour 7: 0.24 µg/mL

Vadhan-Raj Study Design: randomized, crossover study Fosaprepitant: NR Ifosfamide Geometric Mean Cmax: Clinically 12 a (2015) NR NR significant ?: No

[abstract] Objective: to examine the effects of fosaprepitant Ifosfamide: NR Ifosfamide Geometric Mean AUC0-last: single dose versus 2 doses on CINV and ifosfamide NR NR Funding Source: NR

and its metabolites Concomitant Medications: NR Ifosfamide t1/2: NR NR Confounding b Population: patients planned to receive Ifosfamide CL: factors : none anthracycline-ifosfamide therapy 73.9 mL/min 119.3 mL/min reported - N: 47 (40 patients received at least one Ifosfamide GMR Cmax with/without cycle of treatment) fosaprepitant: Adverse events

- Age: NR NR associated with - M:F = NR aprepitant-drug Ifosfamide GMR AUC with/without 0-last interaction: none fosaprepitant: observed/ reported 2-doses: 1.20 (95% CI: 1.09-1.32) 2 doses, 4-hydroxyifosfamide: 0.91 (95% CI: 0.75-1.10) Aprepitant + Pazopanib 13 Imbs (2016) Study Design: open label, non-randomized, dose Aprepitant: Day 1: 125 mg PO Pazopanib Mean Cmax: Clinically a escalation, and PK phase I study (drug interaction once; Days 2 and 3: 80 mg PO NR NR significant ?: UTD

evaluated using crossover design) once daily Pazopanib Mean AUC0-last: - Regular Sequence (RegS): Pazopanib NR NR Funding Source:

started 8 days before adding cisplatin on Pazopanib: 200, 400, or 600 mg Pazopanib Mean t1/2: GlaxoSmithKline and Day 1 PO once daily starting Day -8 NR NR Ligue Nationale - Reverse Sequence (RS): Cisplatin given (RegS) or Day 8 (RS) Pazopanib Mean Change of oral CL: Contre le Cancer

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Aprepitant and Interacting First Author Pharmacokinetic Parameters Significance and Study Design, Objective, and Population Drug’s Dose + Concomitant (Year) Comments Medications Without aprepitant With aprepitant first on Day 1 and pazopanib started on Cycle 1 (RegS): Between Day 0 and: Day 8 Concomitant Medications: Day - Day 1: -24.8% (95% CI: -50.3% to 0.7%) Confounding 1: Cisplatin 60 or 75 mg/m2 IV - Day 2: -32.9% (95% CI: -55.6% to - factorsb: Objective: to determine the maximum tolerated once, Methylprednisolone 80 10.2%) methylprednisolone dose of pazopanib and cisplatin given in mg IV once, granisetron 3 mg IV (oral clearance of pazopanib decreased) combination; secondary objective was to once Cycle 2 (RegS): Between Day 0 and : Adverse events characterize pharmacokinetics of the combination - Day 1: -37.3% (95% CI: -97.5% to associated with 22.9%) aprepitant-drug

Mean Pazopanib Cmin,ss (±SD): interaction: authors Population: solid malignancy Cycle 1 (RegS) concluded that - N: 35 (26 RegS, 9 RS; 3 patients - Day 0: 20.5 ± 12.5 µg/mL observed increase in treatment interrupted before cisplatin - Day 1 (before cisplatin): 18.3 ± 8.9 exposure to administration) µg/mL pazopanib - Median age: 56 years (range: 24-72 - Day 2: 24.2 ± 11.6 µg/mL (p<0.001 vs contributed to its years) Day 1) poor tolerance - M:F = 22:13 - Day 3: 26.5 ± 12.7 µg/mL (p<0.001 vs Day 1) - Day 8: 13.9 ± 5.0 µg/mL Cycle 2 (RegS) - Day 0: 14.6 ± 7.6 µg/mL - Day 1 (before cisplatin): 13.5 ± 5.3 µg/mL - Day 2: 19.9 ± 8.8 µg/mL (p<0.001 vs Day 1) - Day 8: 12.8 ± 5.0 µg/mL

Pazopanib GMR Cmax with/without aprepitant: NR

Pazopanib GMR AUC0-last with/without aprepitant: NR Aprepitant + Thiotepa

De Jonge Study Design: prospective pharmacokinetic study Aprepitant: Day -1: 125 mg PO Thiotepa Mean Cmax: Clinically 6 a (2005) with historical control (2 patients received 80 mg PO); NR NR significant ?: UTD

- G1: patients receiving aprepitant and 4- Days 1 to 7: 80 mg PO once Thiotepa Mean AUC0-last: day course of either cyclophosphamide, daily NR NR Funding Source: thiotepa and carboplatin (CTC) or tCTC Dutch Cancer Society Thiotepa Mean t1/2: (1/3 dosing of CTC) CTC (n=6): NR NR - G2: 49 patients who had received same Days 1 to 4: Confounding CL of thiotepa to tepa:

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Aprepitant and Interacting First Author Pharmacokinetic Parameters Significance and Study Design, Objective, and Population Drug’s Dose + Concomitant (Year) Comments Medications Without aprepitant With aprepitant 2 chemotherapy regimen without CPA: 1500mg/m /day IV 11.2 L/h 7.49 L/h factorsb: aprepitant sampled under same carboplatin IV (dose calculated dexamethasone based on modified Calvert conditions Thiotepa GMR Cmax with/without aprepitant: formula, using target AUC of 5 mg min/mL/day) NR Objective: to determine the influence of 2 Adverse events thiotepa: 120 mg/m /day IV Thiotepa GMR AUC0-last with/without aprepitant: aprepitant on the bioactivation of q12h NR associated with cyclophosphamide and the metabolism of aprepitant-drug thiotepa. Findings with respect to tCTC (n=2): same as CTC except Inhibition of thiotepa metabolism to tepa interaction: NR cyclophosphamide are summarized elsewhere in doses reduced by 1/3 resulted in a 15% higher total thiotepa exposure

this table. and a 20% lower tepa exposure Concomitant medications: Population: breast cancer or germ cell cancer mesna 500 mg IV 6x/day x36 - N: 8 doses; ciprofloxacin PO and - Median age: NR (range: NR) fluconazole PO (starting 4 days - M:F = 1:7 prior to chemotherapy); ranitidine; fytomenadion; folic acid; granisetron 1 mg IV BID and dexamethasone 10 mg IV BID on 4 days of chemotherapy, followed by 1 mg granisetron IV BID and dexamethasone 10 mg IV once daily for 2 days after chemotherapy.

Note: dexamethasone doses in patients receiving aprepitant were not decreased Aprepitant + Vinorelbine 14 Loos (2007) Study Design: open-label, balanced, two-period Aprepitant: Day 1: 125 mg PO Vinorelbine Geometric Mean Cmax: Clinically a crossover study once; Days 2 and 3: 80 mg PO 631.9 ng/mL (90% CI: 733.3 ng/mL (90% CI: significant ?: No once daily 551.0-724.9 ng/mL) 639.3-841.1 ng/mL)

Objective: to determine potential interaction of 3- Vinorelbine Geometric Mean AUC0-inf: Funding Source: NR. day aprepitant (+ ondansetron and Vinorelbine: Days 1, 8 and 15: 584.8 ng∙h/mL (90% 589.4 ng∙h/mL (90% Co-investigator are 2 dexamethasone) with vinorelbine 25 mg/m IV once CI: 497.9-687.0 CI: 501.8-692.3 Merck & Co. Inc. ng∙h/mL) ng∙h/mL) employees Population: advanced malignant solid tumors Concomitant medications: Day Vinorelbine Harmonic Mean t1/2 (± pseudo SD):

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- N: 14 (12 patients completed study) 1: dexamethasone 12 mg PO Alpha t1/2: 0.07 ± 0.02 Alpha t1/2: 0.06 ± 0.01 Confounding - Median age: 56 years (range: NR) once, ondansetron 32 mg IV h h factorsb: - M:F = 4:8 once (only given during Beta t1/2: 1.1 ± 0.3 h Beta t1/2: 1.2 ± 0.5 h dexamethasone, aprepitant treatment arm); Gamma t1/2: 21.4 ± 8.8 Gamma t1/2: 17.1 ± 7.0 ondansetron Days 2 to 4: dexamethasone 8 h h mg PO once Vinorelbine Geometric Mean CL: Adverse events 78.0 L/h (90% CI: 77.4 L/h (90% CI: associated with 65.5-92.8 L/h) 65.0- 92.1 L/h) aprepitant-drug

Vinorelbine GMR Cmax with/without aprepitant: interaction: NR 1.16 (90% CI: 1.01-1.33)

Vinorelbine GMR AUC0-inf with/without aprepitant: 1.01 (90% CI: 0.93-1.10) Drug Interaction Mechanism Unknown Aprepitant + Melphalan 15 Egerer (2010) Study Design: pharmacokinetic comparison sub- Aprepitant: Day 1: 125 mg PO Melphalan Mean Cmax (±SD): Clinically a study of a prospective, placebo-controlled, once; Days 2 and 3: 80 mg PO 3269± 660 ng/mL 3431 ± 608 ng/mL significant ?: UTD

randomized, double-blind study once daily Melphalan Mean AUC0-inf (±SD): 6213±1724 ng∙h/mL 5711±1342 ng∙h/mL Funding Source: MSD Objective: To assess the effect of aprepitant on the Melphalan: Days 1 and 2: 100 Sharp & Dohme Melphalan Mean t1/2 (±SD): pharmacokinetics of high-dose melphalan mg/m2 IV once 1.30 ± 0.18 h 1.28 ± 0.19 h Confounding Melphalan Mean CL (±SD): b Population: multiple myeloma Concomitant Medications: 2 2 factors : digoxin PO - N: 30 (10 aprepitant arm, 20 placebo Day 1: granisetron 2 mg once, 17.3 ± 4.7 L/h∙m 18.2 ± 3.5 L/h∙m Melphalan Arithmetic Cmax with/without arm) dexamethasone 8 mg once c Adverse events - Mean age: Days 2 to 3: granisetron 2 mg aprepitant : associated with o Aprepitant arm: 57.4 years once daily, dexamethasone 4 1.05 aprepitant-drug (range: 40-69 years) mg once daily Melphalan Arithmetic AUC0-inf with/without interaction: NR c o Placebo arm: 62.1 years Day 4: granisetron 2 mg once aprepitant : (range: 39-71 years) 0.92 - M:F = 19:11 Note: dexamethasone dose reduced by 50% in aprepitant arm; some patients may have received digoxin PO PO, by mouth; IV, intravenously; N, number of study subjects; M, male; F, female; GMR, geometric mean ratio; NR, not reported; PK, pharmacokinetic; inf, infinity; CV%, coefficient of variation; h, hour; TDM, therapeutic drug monitoring; Cminss, trough plasma concentrations at steady state a b Clinical significance is defined by review authors as the geometric mean ratio of with aprepitant/without aprepitant for Cmax or AUC value >1.25 or <0.80, regardless of confidence interval; Confounding factors may include other medications that a study subject may have received that would alter the pharmacokinetic disposition of the interacting drug or anything that was mentioned in the study paper that would impact the pharmacokinetic disposition of the interacting drug; cSystematic review study investigator calculated arithmetic mean ratio (GMR not provided by author in publication)

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Supplementary Table B7. Studies evaluating pharmacokinetic drug interactions between aprepitant or fosaprepitant and non-antineoplastic agents First Aprepitant and Interacting Drug’s Dose Pharmacokinetic Parameters Significance and Author Study Design, Objective, and Population and Concomitant Medications Comments (Year) Without aprepitant With aprepitant Non-Antineoplastic Agents Known to be CYP3A4 Substrates Aprepitant + Dexamethasone PO

McCrea Study Design: open-label, randomized, Aprepitant: Dexamethasone Geometric Mean Cmax: Clinically 16 a (2003) incomplete-block, 3 period crossover design G2 and G3: Day 1: 125 mg PO once; Days Day 1 Day 1 significant ?: Yes (for dexamethasone part of study) 2 and 3: 80 mg PO once daily G1: 178.7 ng/mL (95% G2: 241.7 ng/mL (95% CI: 151.2-210.8 ng/mL) CI: 205.0-285.0 ng/mL) Funding Source: Objective: to determine effects of aprepitant Dexamethasone: G3: 152.2 ng/mL (95% Merck & Co, Inc. on dexamethasone pharmacokinetics in triple- G1: Day 1: 20 mg PO once; Days 2 to 5: 8 CI: 129.1-179.5 ng/mL) therapy dosing regimen (aprepitant, mg PO once daily Day 5 Day 5 Confounding b dexamethasone, and ondansetron) and G2: Day 1: 20 mg PO once; Days 2 to 5: 8 G1:58.1 ng/mL (95% CI: G2: 88.2 ng/mL (95% CI: factors : methylprednisolone pharmacokinetics. mg PO once daily 47.7-70.7 ng/mL) 72.5-107.4 ng/mL) dexamethasone Findings with respect to methylprednisone are G3: Day 1: 12 mg PO once; Days 2 to 5: 4 G3: 45.9 ng/mL (95% CI: dosing summarized elsewhere in this table. mg PO once daily 37.7-55.8 ng/mL)

Dexamethasone Geometric Mean AUC0-24h : Adverse events Population: healthy subjects Concomitant Medications: Day 1: Day 1 Day 1 associated with - N: 20 ondansetron 32 mg IV G1: 896.7 ng·h/mL (90% G2: 1943.0 ng·h/mL aprepitant-drug - Mean age: 34 years (range: 20-46 CI: 762.6-1054.5 (90% CI: 1652.8-2248.0 interaction: NR years) ng·h/mL) ng·h/mL) - M:F = 12:8 G3: 1160.4 ng·h/mL (986.8-1364.4 ng·h/mL) Day 5 Day 5 G1: 292.4 ng·h/mL (90% G2: 641.8 ng·h/mL (90% CI: 233.0-366.8 CI: 511.8-805.0 ng·h/mL) ng·h/mL) G3: 302.5 ng·h/mL (90% CI: 241.1-379.6 ng·h/mL)

Dexamethasone Harmonic Mean t1/2 (range): Day 1 Day 1 G1: 3.6 h (3.1-4.1 h) G2: 5.4 h (3.3-9.5 h) G3: 5.2 h (3.2-7.1 h) Day 5 Day 5 G1: 3.9 h (2.8-5.1 h) G2: 5.6 h (3.6-9.4 h) G3: 5.3 h (3.4-8.8 h) Dexamethasone Mean CL: NR NR

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Dexamethasone GMR Cmax with/without aprepitant: Day 1 G2 vs. G1: 1.35 (95% CI: 1.12-1.64) G3 vs. G1: 0.85 (95% CI: 0.70-1.03) Day 5 G2 vs. G1: 1.52 (95% CI: 1.21-1.90) G3 vs. G1: 0.79 (95% CI: 0.63-0.99

Dexamethasone GMR AUC0-24h with/without aprepitant: Day 1 G2 vs. G1: 2.17 (90% CI: 1.95-2.40) G3 vs. G1: 1.29 (90% CI: 1.17-1.44); p<0.01 Day 5 G2 vs. G1: 2.20 (90% CI: 1.89-2.55); p<0.01 G3 vs. G1: 1.03 (90% CI: 0.89-1.20); p>0.25

Marbury Study Design: open-label, randomized, 2- Fosaprepitant: Day 1: 150 mg IV once Dexamethasone Geometric Mean Cmax: Clinically 17 a (2011) period crossover study (2 parts: part 1 Day 1: 70.4 ng/mL (95% Day 1: 87.5 ng/mL (95% significant ?: Yes dexamethasone, part 2: midazolam drug Dexamethasone: Days 1 to 3: 8 mg PO CI: 60.9-81.2 ng/mL) CI: 75.8-101 ng/mL) interaction) once daily Day 2: 63.0 ng/mL (95% Day 2: 82.3 ng/mL (95% Funding Source: CI: 54.6-72.7 ng/mL) CI: 71.3-95.0 ng/mL) Merck & Co, Inc.; Objective: (1) to assess the possible drug Concomitant Medications: none Day 3: 57.0 ng/mL (95% Day 3: 67.1 ng/mL (95% co-authors are interaction between fosaprepitant 150 mg IV CI: 49.4-65.8 ng/mL) CI: 58.1-77.5 ng/mL) Merck employees

on day 1 and oral dexamethasone 8 mg on days Dexamethasone Geometric Mean AUC0-24h: 1-3 and (2) to assess the possible interaction Day 1: 364 ng∙h/mL Day 1: 733 ng∙h/mL Confounding b between fosaprepitant 150 mg IV and (95% CI: 308-430 (95% CI: 620-866 factors : none midazolam on days 1 and 4. Findings with ng∙h/mL) ng∙h/mL) reported respect to midazolam are summarized Day 2: 283 ng∙h/mL Day 2: 528 ng∙h/mL elsewhere in this table. (95% CI: 240-335 (95% CI: 447-624 Adverse events ng∙h/mL) ng∙h/mL) associated with Population: healthy, non-smoking adults Day 3: 253 ng∙h/mL Day 3: 298 ng∙h/mL aprepitant-drug - N: 23 (13 enrolled in dexamethasone (95% CI: 214-298 (95% CI: 252-352 interaction: none arm) ng∙h/mL) ng∙h/mL) observed/reported;

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29.7 years (range: 18-45 years) Dexamethasone Harmonic Mean t1/2 (± pseudo with vs without - M:F = 16:7 (10:3 dexamethasone aprepitant NR arm) SD): Day 1: 3.6 ± 0.7 h Day 1: 5.7 ±1.3 h Day 2: 3.0 ± 0.5 h Day 2: 4.0 ±0.9 h Day 3: 3.1 ± 0.6 h Day 3: 3.1 ±0.6 h Dexamethasone Mean CL: NR NR

Dexamethasone GMR Cmax with/without fosaprepitant: Day 1: 1.24 (90% CI: 1.09-1.42) Day 2: 1.31 (90% CI: 1.14-1.49) Day 3: 1.18 (90% CI: 1.03-1.34)

Dexamethasone GMR AUC0-last with/without fosaprepitant: Day 1: 2.01 (90% CI: 1.84-2.20) Day 2: 1.86 (90% CI: 1.71-2.03) Day 3: 1.18 (90% CI: 1.08-1.29) Aprepitant + Dexamethasone IV

Nakade Study Design: PK model development using Aprepitant: Dexamethasone Mean Cmax (±SD): Clinically (2008)18 retrospective data Study 1: 125mg PO once NR NR significanta?: UTD Study 2: 40 mg or 80 mg PO once Dexamethasone Mean AUC0-last (±SD): Objective: to develop a PK model of aprepitant Study 3: Funding Source: NR NR NR using plasma concentrations on two Phase I - G1: none Confounding and Phase II pivotal studies in Japan and to - G2: Day 1: 40 mg PO once; factorsb: none evaluate the effect of aprepitant on the Days 2 to 5: 25 mg PO once Dexamethasone Mean t1/2 (±SD): reported clearance of IV dexamethasone daily NR NR - High dose: Day 1: 125 mg PO Adverse events

Population: Japanese; once; Days 2 to 5: 80 mg PO associated with - Aprepitant: once daily aprepitant-drug o Phase I studies (Study 1 and 2), Dexamethasone: Dexamethasone Mean CL: interaction: NR healthy patients: Study 3: NR With 40 mg aprepitant: . N: 25 - G1: Day 1: 8 mg IV once; Days 24.7% lower than o Phase II study (Study 3), cancer 2 and 3: 12 mg IV once daily dexamethasone alone. patients with solid tumor: - G2: Day 1: 6 mg IV once; Days With 125 mg . N: 290 2 and 3: 8 mg IV once daily aprepitant: 47.5% o Median age: 62 years (range: 20- - G3: Day 1: 4 mg IV once; Days lower than

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o M:F = 246:69 Dexamethasone GMR Cmax with/without - Dexamethasone, cancer patients Concomitant Medications: aprepitant: 2 also receiving aprepitant : Study 3: cisplatin ≥70mg/m IV (first NR o Phase II study (Study 3): dose of cisplatin); Day 1: granisetron IV Dexamethasone GMR AUC0-last with/without . N: 440 40µg/kg once aprepitant: o Median age: 63 years (range: 23- NR 80 years) o M:F = 333:107

Takahashi Study Design: randomized, open-label study Aprepitant: Dexamethasone Mean Cmax (±SD): Clinically 19 a (2011) - Dexamethasone clearance observed G1: Day 1: 125 mg PO once; Days 2 to 5: NR G1: 121 ± 17 ng/mL significant ?: UTD in this study was compared to the 80 mg PO once daily G2: 147 ± 27 ng/mL

findings in a previous study of G2: Day 1: 40 mg PO once; Days 2 to 5: Dexamethasone Mean AUC0-24h (±SD): Funding Source: dexamethasone clearance in 25 mg PO once daily NR G1: 823 ± 213 ng∙h/mL Ono Japanese cancer patients who G2: 838 ± 253 ng∙h/mL Pharmaceutical received dexamethasone 12 mg Dexamethasone: Co., Ltd. and Merck No aprepitant group: Day 1: 12 mg & Co., Inc. Dexamethasone Mean t1/2 (±SD): Objective: to determine PK of aprepitant and (route NR) dexamethasone, and to verify dose reduction G1: Day 1: 6 mg IV once; Days 2 and 3: 4 G1: 9.6 ± 2.4 h Confounding of dexamethasone in combination with mg IV once daily NR G2: 5.7 ± 1.4 h factorsb: aprepitant and in vivo kinetics of substance P G2: Day 1: 8 mg IV once, Days 2 and 3: 6 chemotherapy after administration of chemotherapy mg IV once daily metabolized by Dexamethasone Mean CL (±SD): CYP3A4 Population: Japanese cancer patients receiving Concomitant Medications: G1: 6.48 ± 2.50 L/h chemotherapy Cisplatin + 13.3 L/h G2: 10.0 ± 4.1 L/h Adverse events - N: 20 - Gemcitabine or associated with - Mean age: - Tegafur/gimeracil/oteracil or Dexamethasone GMR Cmax with/without aprepitant-drug o G1: 59.7 years (range: 47-71 - Vinorelbine or aprepitant: interaction: NR years) - Etoposide or o G2: 63.6 years (range: 55-72 - Docetaxel NR years) Dexamethasone GMR AUC with/without - M:F = 13:7 0-last aprepitant:

Aprepitant + Dolasetron 20 Li (2006) Study Design: single-centre, open-label, Aprepitant: Day 1: 125 mg PO once; Hydrodolasetron Geometric Mean Cmax: Clinically a randomized, 2-period crossover trial with Days 2 and 3: 80 mg PO once daily All subjects: 275.1 All subjects: 297.0 significant ?: No washout of at least 14 days between periods ng/mL ng/mL Dolasetron: Day 1: 100 mg PO once Poor metabolizers: Poor metabolizers: Funding Source:

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First Aprepitant and Interacting Drug’s Dose Pharmacokinetic Parameters Significance and Author Study Design, Objective, and Population and Concomitant Medications Comments (Year) Without aprepitant With aprepitant 356.1 ng/mL 401.1 ng/mL Merck & Co., Inc. Objective: to evaluate the potential effect of Concomitant Medications: NR Extensive metabolizers: Extensive metabolizers: aprepitant on the plasma concentration profile 212.4 ng/mL 219.9 ng/mL Confounding of hydrodolasetron (active drug) as well as on b Hydrodolasetron Geometric Mean AUC0-∞: factors : none ECG parameters in CYP2D6 poor and CYP2D6 reported extensive metabolizers All subjects: All subjects:

1747.2 ng·h/mL 1911.1 ng·h/mL Adverse events Population: healthy adults identified as CYP2D6 Poor metabolizers: Poor metabolizers: associated with poor and extensive metabolizers 2913.3 ng·h/mL 3223.7 ng·h/mL aprepitant-drug - N: 14 (12 patients completed study; Extensive metabolizers: Extensive metabolizers: interaction: none 6 CYP2D6 poor metabolizers and 6 1047.9 ng·h/mL 1132.9 ng·h/mL observed/ reported CYP2D6 extensive metabolizers) Hydrodolasetron Arithmetic Mean t1/2 (±SD): - Mean age: NR (range: 19-52 years) All subjects: 12.6 ± 3.6 h All subjects: 11.7 ± 5.0 - M:F = 8:4 of those who completed Poor metabolizers: 13.2 h study ± 4.4 h Poor metabolizers: 12.4 Extensive metabolizers: ± 2.6 h Extensive metabolizers: 12.1 ± 2.9 h 11.0 ± 6.8 h Hydrodolasetron Geometric Mean CL (±SD):

NR NR

Hydrodolasetron GMR Cmax with/without aprepitant: All subjects: 1.08 (90% CI: 0.94-1.24) Poor metabolizers: 1.13 (90% CI: 0.92-1.38) Extensive metabolizers: 1.04 (90% CI: 0.84-1.27)

Hydrodolasetron GMR AUC0-last with/without aprepitant: All subjects: 1.09 (90% CI: 1.01-1.18) Poor metabolizers: 1.11 (90% CI: 0.98-1.25) Extensive metabolizers: 1.08 (90% CI: 0.96-1.22) Aprepitant + Granisetron

Blum Study Design: randomized, open-label, 2- Aprepitant: Day 1: 125 mg PO once; Granisetron Geometric Mean Cmax: Clinically 21 a (2003) period crossover study (for granisetron part of Days 2 and 3: 80 mg PO once daily 9.0 ng/mL 9.0 ng/mL significant ?: No

study) Granisetron Geometric Mean AUC0-∞: Granisetron: Day 1: 2 mg PO once 92.2 ng∙h/mL 101.4 ng∙h/mL Funding Source: Objective: to assess the effect of oral NR, Granisetron Harmonic Mean t1/2:

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First Aprepitant and Interacting Drug’s Dose Pharmacokinetic Parameters Significance and Author Study Design, Objective, and Population and Concomitant Medications Comments (Year) Without aprepitant With aprepitant aprepitant on PK of oral granisetron and Concomitant Medications: NR 6.9 h 6.5 h acknowledgment ondansetron. Findings with respect to Granisetron Mean CL: to Merck & Co., ondansetron are summarized elsewhere in this NR NR Inc. for review of table. assay methods Granisetron GMR Cmax with/without aprepitant: 1.0 (90% CI: 0.87-1.13) Population: healthy Confounding - N: 18 (17 included in analysis) factorsb: none Granisetron GMR AUC0--∞ with/without aprepitant:

- Mean age: 27.9 years (range: 18-44 1.10 (90% CI: 0.96-1.26) reported years) - M:F = 11:7 Adverse events associated with aprepitant-drug interaction: NR Aprepitant + Methylprednisolone 16 McCrea Study Design: double-blind, randomized, Aprepitant: Day 1: 125 mg PO once; Methylprednisolone Geometric Mean Cmax: Clinically a placebo-controlled, 2-period crossover design Days 2 and 3: 80 mg PO once daily Day 1 (eoi): 8532.2 Day 1 (eoi): 6645.8 significant ?: Yes with at least 12 days between regimens (for ng/mL (95% CI: 7153.9- ng/mL (95% CI: 5572.3- methylprednisolone part of study) Methylprednisolone: Day 1: 125 mg IV 10176.0 ng/mL) 7926.2 ng/mL) Funding Source: once; Days 2 and 3: 40 mg PO once daily Day 3: 341.6 ng/mL Day 3: 498.9 ng/mL Merck & Co., Inc Objective: to determine effects of aprepitant (95% CI: 287.6-405.9 (95% CI: 420.0-592.7 on methylprednisolone pharmacokinetics and Concomitant Medications: NR ng/mL) ng/mL) Confounding dexamethasone pharmacokinetics in triple- factorsb: none Methylprednisolone Geometric Mean AUC0-24h: therapy dosing regimen (aprepitant, Day 1: 6822.1 ng·h/mL Day 1: 9122.8 ng·h/mL reported dexamethasone, and ondansetron). Findings (95% CI: 5646.4-8242.6 (95% CI: 7550.6- with respect to dexamethasone are ng·h/mL) 11022.4 ng·h/mL) Adverse events summarized elsewhere in this table. Day 3: 1404.8 ng·h/mL Day 3: 3462.1 ng·h/mL associated with (95% CI: 1098.5-1796.5 (95% CI: 2707.2-4427.6 aprepitant-drug Population: healthy ng·h/mL) ng·h/mL) interaction: NR - N: 10 Methylprednisolone Harmonic Mean t1/2 (range): - Mean age: 31 years (range: 20-44 Day 1: 2.0 h (1.4-2.7 h) Day 1: 3.5 h (2.0-5.0 h) years) Day 3: 2.1 h (1.3-2.5 h) Day 3: 3.7 h (1.9-6.4 h) - M:F =8:2 Methylprednisolone Geometric Mean CL Day 1 (post-hoc analysis): 306.4 mL/min (95% CI: 229.5 mL/min (95%CI: 259.3-362.0 mL/min) 194.2-271.2 mL/min)

Methylprednisolone GMR Cmax with/without aprepitant:

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Methylprednisolone GMR AUC0-24h with/without aprepitant: Day 1: 1.34 (95% CI: 1.17-1.52) Day 3: 2.46 (95% CI: 2.24-2.72) Aprepitant + Midazolam

Majumdar Study Design: open-label, randomized, Aprepitant: Midazolam Geometric Mean C1h: Clinically 22 a (2003) crossover, single-period study design Period 1: G1 and G2: no aprepitant G1: 8.6 ng/mL (95% CI: G1: significant ?: Yes Period 2: G1: 40 mg PO once; Days 2 to 7.0-10.5 ng/mL) Day 1: 10.4 ng/mL (95% (with aprepitant Objective: to evaluate the effects of aprepitant 5: 25 mg PO once daily CI: 8.4-12.7 ng/mL) 125 Day 1, 80 mg on CYP3A4 activity G2: Day 1: 125 mg PO once; Days 2 to 5: Day 5: 9.0 ng/mL (95% Days to 5) 80 mg PO once daily CI: 7.4-11.1 ng/mL) Population: healthy, nonsmokers G2: 8.1 ng/mL (95% CI: G2: Funding Source: - N: 16 Midazolam: 6.0-10.8 ng/mL) Day 1: 11.8 ng/mL (95% Merck & Co., Inc. - Mean age: 30 years (range: 20-43 Period 1: 2 mg once 3-7 days before CI: 8.8-15.7 ng/mL) years) aprepitant; Day 5: 15.7 ng/mL (95% Confounding b - M:F = 16:0 Period 2: G1 and G2: Day 1 and Day 5: 2 CI: 11.7-20.9 ng/mL) factors : none

mg PO once Midazolam Geometric Mean AUC0-∞: reported G1: G1: Concomitant Medications: NR 30.8 ng·h/mL (95% CI: Day 1: 37.7 ng·h/mL Adverse events 22.0-43.1 ng·h/mL) (95% CI: 26.9-52.7 associated with ng·h/mL) aprepitant-drug Day 5: 31.4 ng·h/mL interaction: none G2: (95% CI: 22.5-43.9 observed/reported 23.0 ng·h/mL (95% CI: ng·h/mL) 17.7-29.7 ng·h/mL) G2: Day 1: 52.1 ng·h/mL (95% CI: 40.2-67.6 ng·h/mL) Day 5: 75.7 ng·h/mL (95% CI: 58.4-98.1 ng·h/mL)

Midazolam Harmonic Mean t1/2 (range): G1: G1: 2.26 h (1.2-3.7 h) Day 1: 2.59 h (1.2-5.2 h) Day 5: 2.00 h (1.0-4.6 h) G2: 1.69 h (1.0-2.5 h) G2:

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Midazolam GMR C1h with/without aprepitant: Aprepitant 40/25: Day 1: 1.21 (95% CI: 0.91-1.61) Day 5: 1.05 (95% CI: 0.79-1.40) Aprepitant 125/80: Day 1: 1.46 (95% CI: 1.01-2.09) Day 5: 1.94 (95% CI: 1.35-2.78)

Midazolam GMR AUC0-∞ with/without aprepitant: Aprepitant 40/25: Day 1: 1.22 (95% CI: 0.93-1.61) Day 5: 1.02 (95% CI: 0.77-1.35) Aprepitant 125/80: Day 1: 2.27 (95% CI: 1.64-3.14) Day 5: 3.30 (95% CI: 2.39-4.56)

Shadle Study Design: double-blind, placebo-controlled Aprepitant: G1: Day 1: 125 mg PO once; Midazolam Geometric Mean Cmax: Clinically 23 a (2004) study Day 2 and 3: 80 mg PO once daily Baseline: 134 ng/mL Baseline: 116 ng/mL significant ?: Yes G2: placebo Day 4: 124 ng/mL Day 4: 85 ng/mL Objective: to assess effects of aprepitant on Day 8: 112 ng/mL Day 8: 105 ng/mL Funding Source: CYP3A4 and CYP2C9 over 2 weeks. Findings Day 15: 120 ng/mL Day 15: 113 ng/mL Merck * Co., Inc.

with respect to tolbutamide are reported Midazolam: G1 and G2: Baseline (Days -7 Midazolam Geometric Mean AUC0-∞: elsewhere. to -5), Days 4, 8 and 15: 2 mg IV once Baseline: 72.7 ng·h/mL Baseline: 70.2 ng·h/mL Confounding b Day 4: 76.9 ng·h/mL Day 4: 92.5 ng·h/mL factors : none Population: healthy, non-smoking subjects Concomitant Medications: G1 and G2: Day 8: 73.7 ng·h/mL Day 8: 57.4 ng·h/mL reported - N: 24 Baseline (Days -7 to -5), Days 4, 8 and Day 15: 72.5 ng·h/mL Day 15: 67.6 ng·h/mL - Mean age (range): 15: tolbutamide 500mg PO once Adverse events Midazolam Median t1/2: o G1: 29 years (18-40 years) Baseline: 4.15 h Baseline: 4.25 h associated with o G2: 29 years (21-44 years) Day 4: 4.25 h Day 4: 4.15 h aprepitant-drug - M:F = Day 8: 3.50 h Day 8: 4.15 h interaction: none o G1: 9:3 Day 15: 3.95 h Day 15: 4.15 h observed/reported o G2: 8:4 Midazolam Geometric Mean CL (no units provided): Baseline: 458 Baseline: 475 Day 4: 434 Day 4: 360 Day 8: 452 Day 8: 581

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Midazolam GMR Cmax with/without aprepitant: Day 4: 0.80 (90% CI: 0.41-1.54) Day 8: 1.08 (90% CI: 0.56-2.08) Day 15: 1.09 (90% CI: 0.57-2.10)

Midazolam GMR AUC0-∞ with/without aprepitant: Day 4: 1.25 (90% CI: 1.09-1.42) Day 8: 0.81 (90% CI: 0.71-0.92) Day 15: 0.96 (90% CI: 0.85-1.10)

Majumdar Study Design: open-label, single-centre, Aprepitant: 125 mg PO once 1 hour prior Midazolam Geometric Mean Cmax: Clinically 24 a (2007) randomized, 2-period, crossover study with at to midazolam 59.7 ng/mL 71.8 ng/mL significant ?: Yes

least 14 days between regimens Midazolam Geometric Mean AUC0-∞: Midazolam: 2 mg IV once 75.0 ng·h/mL 110.3 ng·h/mL Funding Source: Objective: to evaluate the effect of a single Merck Research Midazolam Harmonic Mean t1/2: dose of oral aprepitant 125 mg on CYP3A4 Concomitant Medications: NR Laboratories 5.2 h activity as measured by the pharmacokinetics 3.7 h of IV midazolam Confounding b Midazolam Geometric Mean CL: factors : none Population: healthy patients, non-smokers 302.1 mL/min - N: 13 (12 subjects completed study) 444.5 mL/min Adverse events - Median age: NR (range: 20-36 years) associated with - M:F = 3:9 Midazolam GMR Cmax with/without aprepitant: aprepitant-drug c 1.20 interaction: one Midazolam GMR AUC0-∞ with/without aprepitant: subject had 1.47 (90% CI: 1.36-1.59) lightheadedness, fatigue and disorientation with midazolam + aprepitant that study authors believed to be drug-related (not specifically stated as being attributed to drug interaction)

Stoch Study Design: double-blind, 2-period crossover Aprepitant: Period 1: Day 1: 125 mg PO Midazolam Mean Cmax: Clinically 25 a (2011) study once; Days 2 and 3: 80 mg PO once daily NR NR significant ?: Yes

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Period 2: placebo Midazolam Mean AUC0-∞(±SD): Objective: to assess whether aprepitant added Oral midazolam: Oral midazolam: Funding Source: to a 5-HT3 antagonist and glucocorticoid would Midazolam: Periods 1 and 2: Day -1, 6, 8 Baseline: 19.8 ± 6.3 Baseline: 20.9 ± 11.2 Merck Research affect CYP3A4 induction 15 and 22: 2 mg PO and IV once. IV dose ng·h/mL ng·h/mL Laboratories was radiolabelled. Day 6: 16.6 ± 6.8 Day 6: 17.5 ± 9.6 Population: healthy ng·h/mL ng·h/mL Confounding b - N: 12 Concomitant Medications: Day 8: 28.8 ± 12.9 Day 8: 19.0 ± 7.2 factors : - Mean age: 34 years (range: 22-44 Period 1: Day 1: ondansetron 32 mg IV ng·h/mL ng·h/mL dexamethasone years) once, dexamethasone 12 mg PO once; Day 15: 27.8 ± 12.4 Day 15: 19.4 ± 5.8 - M:F = 10:2 Days 2 to 4: dexamethasone 8 mg PO ng·h/mL ng·h/mL Adverse events once daily Day 22: 23.4 ± 7.6 Day 22: 17.3 ± 5.7 associated with Period 2: Day 1: dexamethasone 12 mg ng·h/mL ng·h/mL aprepitant-drug PO once; Days 2 to 4: dexamethasone 8 IV midazolam: IV midazolam: interaction: none mg PO BID Baseline: 38.1 ± 7.6 Baseline: 39.5 ± 12.3 observed/reported ng·h/mL ng·h/mL Day 6: 39.0 ± 9.4 Day 6: 35.5 ± 9.7 ng·h/mL ng·h/mL Day 8: 47.7 ± 14.1 Day 8: 36.8 ± 8.4 ng·h/mL ng·h/mL Day 15: 43.6 ± 13.7 Day 15: 35.6 ± 7.2 ng·h/mL ng·h/mL Day 22: 40.8 ± 5.0 Day 22: 37.2 ± 9.3 ng·h/mL ng·h/mL

Midazolam Mean t1/2: NR NR Midazolam Mean CL: NR NR

Midazolam GMR Cmax with/without aprepitant: NR

Midazolam GMR AUC0-∞ with/without aprepitant: Oral midazolam: Day 6: 1.00 (90% CI: 0.80-1.25) Day 8: 0.63 (90% CI:0.49-0.78)

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First Aprepitant and Interacting Drug’s Dose Pharmacokinetic Parameters Significance and Author Study Design, Objective, and Population and Concomitant Medications Comments (Year) Without aprepitant With aprepitant Day 15: 0.66 (90% CI: 0.53-0.83) Day 22: 0.70 (90% CI: 0.56-0.88) IV midazolam: Day 6: 0.88 (90% CI: 0.74-1.03) Day 8: 0.74 (90% CI: 0.63-0.87) Day 15: 0.79 (90% CI: 0.67-0.93) Day 22: 0.88 (90% CI: 0.75-1.04)

Marbury Study Design: open-label, randomized, 2- Fosaprepitant: Day 1: 150 mg IV once Midazolam Geometric Mean Cmax: Clinically 17 a (2011) period crossover study (2 parts: part 1 Day 1: 8.33 ng/mL Day 1: 9.73 ng/mL significant ?: Yes dexamethasone, part 2: midazolam drug Midazolam: Day 1 and 4: 2 mg PO once (95% CI: 6.39-10.9 (95% CI: 7.46-12.7 interaction) ng/mL) ng/mL) Funding Source: Concomitant Medications: none Day 4: 8.82 ng/mL Day 4: 8.42 ng/mL Merck & Co., Inc. Objective: (1) to assess the possible drug (95% CI: 6.76-11.5 (95% CI: 6.46-11.0 interaction between fosaprepitant 150 mg IV ng/mL) ng/mL) Confounding b on day 1 and oral dexamethasone 8 mg on days factors : none 1-3 and (2) to assess the possible interaction

between fosaprepitant 150 mg IV and oral Midazolam Geometric Mean AUC0-24h: Adverse events midazolam on days 1 and 4. Findings with Day 1: 28.0 ng·h/mL Day 1: 49.4 ng·h/mL associated with respect to dexamethasone are reported (95% CI: 18.6-42.0 (95% CI: 32.9-74.3 aprepitant-drug elsewhere in this table. ng·h/mL) ng·h/mL) interaction: none Day 4: 27.2 ng·h/mL Day 4: 27.7 ng·h/mL observed/reported; Population: healthy, non-smoking adults (95% CI: 18.1-40.9 (95% CI: 18.4-41.7 differences in AE - N: 23 (10 enrolled in midazolam arm) ng·h/mL) ng·h/mL) with vs without - Mean age for midazolam arm: 30.1 aprepitant NR years (range: 18-44 years) Midazolam Harmonic Mean t1/2 (± pseudo SD): - M:F =16:7 (6:4 midazolam arm) Day 1: 4.6 h (2.0 h) Day 1: 6.2 h (3.4 h) Day 4: 3.8 h (2.3 h) Day 4: 3.7 h (2.2 h) Midazolam Mean CL: NR NR

Midazolam GMR Cmax with/without fosaprepitant: Day 1: 1.17 (90% CI: 0.98-1.38) Day 4: 0.96 (90% CI: 0.81-1.13)

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Midazolam GMR AUC0-24h with/without fosaprepitant: Day 1: 1.77 (90% CI: 1.52-2.05) Day 4: 1.02 (90% CI: 0.88-1.18) Aprepitant + Ondansetron

Blum Study Design: randomized, open-label, 3- Aprepitant: Day 1: 375 mg PO once; Ondansetron Geometric Mean Ceoi: Clinically 21 a (2003) period crossover study with a washout period Days 2 to 5: 250 mg PO once daily 408.4 ng/mL 360.8 ng/mL significant ?: No

of at least 14 days (for ondansetron part of Ondansetron Geometric Mean AUC0-∞: study) Ondansetron: Day 1: 32 mg IV once 1268.3 ng∙h/mL 1456.5 ng∙h/mL Funding Source: NR, Objective: to examine the effect of a Concomitant Medications: Day 1: acknowledgment Ondansetron Harmonic Mean t : supratherapeutic dose of aprepitant on the dexamethasone 20 mg PO once; Days 2 1/2 to Merck & Co., pharmacokinetics of ondansetron and to to 5: 8 mg PO once daily 5.0 h Inc. examine effect of aprepitant on 4.5 h pharmacokinetics of granisetron. Findings with Confounding respect to gransietron are summarized Ondansetron Mean CL: factorsb: elsewhere in this table. NR NR dexamethasone

Population: healthy Ondansetron GMR Cmax with/without aprepitant: Adverse events - N: 19 (15 completed study) associated with - Mean age: 34.4 years (range: 19-46 aprepitant-drug 0.88 (95% CI: 0.70-1.12) years) interaction: NR - M:F = 9:10

Ondansetron GMR AUC0-∞with/without aprepitant:

1.15 (90% CI: 1.05-1.26) Aprepitant + Oxycodone

Fujiwara Study Design: open-label, two-period, single- Aprepitant: Day 1: 125 mg PO; Days 2 Oxycodone Geometric Mean Cmax (CV%): Clinically 26 a (2014) sequence and 3: 80 mg PO 2.28 ng/mL (31.4) 2.79 ng/mL (28.0) significant ?: Yes

Objective: to investigate effects of aprepitant Oxycodone: 5mg to 20 mg/dose PO q8- Funding Source: on the PK of controlled-release PO oxycodone 12h Ministry of Health, - Median daily dose: 20 mg Labour and Population: stage IV cancer receiving chronic - Mean daily dose: 21.5 mg Welfare of Japan oxycodone - Median dose: 10 mg and Yokoyama-

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years) Concomitant Medications (potentially): Oxycodone + metabolites Geometric Mean AUC0-8h Confounding - M:F = 17:3 dexamethasone, 5-HT3 antagonist, (CV%): factorsb: platinum agent, gemcitabine, Oxycodone: 882 Oxycodone: 1102 dexamethasone fluorpyrimidine, taxanes, anthracyclines, ng∙h/mL (35.7) ng∙h/mL (29.9) irinotecan, sunitinib Noroxycodone: Noroxycodone: Adverse events 718 ng∙h/mL (45.2) 616 ng∙h/mL (51.6) associated with Oxymorphone (N=15, Oxymorphone (N=15, aprepitant-drug patients receiving patients receiving interaction: none oxycodone 5 mg q12h oxycodone 5 mg q12h observed/reported excluded due to below excluded due to below LLQ): 14.9 ng∙h/mL LLQ): 20.7 ng∙h/mL (78.0) (65.8)

Mean t1/2: NR NR Mean CL: NR NR

Oxycodone GMR Cmax with/without aprepitant Oxycodone: 1.22 (95% CI: 1.11-1.34)

Oxycodone + metabolites GMR AUC0-8h with/without aprepitant Oxycodone: 1.25 (95% CI: 1.14-1.36) Noroxycodone: 0.86 (95% CI: 0.81-0.91) Oxymorphone: 1.34 (95% CI: 1.20-1.49) Aprepitant + Palonosetron

Shah Study Design: single-centre, open-label, Aprepitant: Day 1: 125 mg PO once; Palonosetron Geometric Mean Cmax: Clinically 27 a (2005) randomized, two-way, crossover trial with a 14 Days 2 and 3: 80 mg PO once daily 1700 ng/L 1680 ng/L significant ?: No

day washout period. Palonosetron Geometric Mean AUC0-∞: Palonosetron: Day 1: 0.25 mg IV once 32900 ng∙h/L 33200 ng∙h/L Funding Source: Objective: to evaluate the PK and safety profile MGI PHARMA, INC. of a single IV dose of palonosetron Concomitant Medications: NR Palonosetron Mean t1/2 (CV%):

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First Aprepitant and Interacting Drug’s Dose Pharmacokinetic Parameters Significance and Author Study Design, Objective, and Population and Concomitant Medications Comments (Year) Without aprepitant With aprepitant administered with and without concomitant 40.0 h (26) Confounding b aprepitant in healthy volunteers 43.0 h (32) factors : none

Population: healthy Palonosetron Mean CL (CV%): Adverse events - N: 12 136 mL/min (43) 130 mL/min (28) associated with - Mean age: 29.9 years (range: NR) aprepitant-drug - M:F = 7:5 Palonosetron GMR Cmax with/without aprepitant: interaction: none reported/observed

0.986 (90% CI: 0.618-1.570)

Palonosetron GMR AUC0-∞ with/without

aprepitant:

1.01 (90% CI: 0.856-1.190) Aprepitant + Prednisolone

Maie Study Design: nonrandomized, open-label, Aprepitant: Period 2: Day 1: 125 mg PO Prednisolone Mean Cmax (±SD): Clinically 28 a (2014) single-group before/after study design once; Days 2 and 3: 80 mg PO once daily 646±191 ng/mL 634±285 ng/mL significant ?: UTD

[letter to between 2 courses of R-CHOP Prednisolone Mean AUC0-5h (±SD): editor] Prednisolone: Period 1 and 2: Days 1 to 2200±490 ng∙h/mL 2178±794 ng∙h/mL Funding Source: Objective: to evaluate effect of aprepitant on 5: 60 mg PO at 08:00h and 40 mg PO at NR; Ono PK of prednisolone and safety and efficacy of 13:00h Pharmaceutical Prednisolone Mean t (±SD): aprepitant when given with rituximab, 1/2 contributed to cyclophosphamide, doxorubicin, vincristine and Concomitant Medications: Period 1 and NR study design prednisolone (R-CHOP) 2: Day 1: granisetron 3 mg BID NR Confounding Population: lymphoma Prednisolone Mean CL (±SD): factorsb: PK - N: 10 (8 patients included in PK NR NR assessed over 5 analysis) hours - Median age: NR (range: NR) Prednisolone GMR Cmax with/without aprepitant: - M:F = NR Adverse events associated with 0.98c aprepitant-drug interaction: none observed/reported Prednisolone GMR AUC0-5h with/without

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0.99c Aprepitant + Quetiapine

Verwimp- Study design: case report Aprepitant: Day 1: 125 mg PO once; Quetiapine Mean Cmax (±SD): Clinically Hoeks Days 2 and 3: 80 mg PO once daily NR NR significant? UTD 28 (2012) Objective: to describe a patient case with a Quetiapine Mean AUC0-t (±SD): [letter to suspected aprepitant-quetiapine drug Quetiapine: Chemotherapy blocks 1 and NR NR Funding source: NR editor] interaction 2: 50 mg PO daily; Chemotherapy block Quetiapine Mean t1/2 (±SD): 3: 25 mg PO daily Confounding NR NR Population: laryngeal carcinoma + depression + factors: Quetiapine Mean CL (±SD): anxiety Concomitant Medications: cisplatin 100 dexamethasone - N: 1 mg/m2 q3weeks, dexamethasone, NR NR - Mean Age: 44 years ondansetron, citalopram Quetiapine GMR Cmax with/without aprepitant: Adverse events - M:F = 1:0 NR associated with QuetiapineGMR AUC0-t with/without aprepitant-drug aprepitant: interaction: NR deep somnolence Quetiapine Concentration: during chemo- 5 µg/L 55 µg/L therapy blocks 1 and 2; no adverse event during chemotherapy block 3

DIPS Score: 6 Aprepitant + Tacrolimus

Ibrahim Study Design: retrospective review Aprepitant: Day 1: 125 mg PO once; Tacrolimus Mean Cmax: Clinically 29 a (2008) Days 2 and 3: 80 mg PO once daily NR NR significant ?: UTD

Objective: to examine the effect of aprepitant Tacrolimus Mean AUC0-last: on the PK disposition of IV tacrolimus in Tacrolimus: starting Day -6: 0.03 NR NR Funding Source: reduced intensity HSCT patients mg/kg/day (using lean body weight) IV none Tacrolimus Mean t1/2: continuous infusion NR Population: reduced intensity HSCT patients Confounding NR b - N: 26 Concomitant Medications: factors : - Median age: 52.5 years (range: 18-68 Day -10: phenytoin 15 mg/kg IV once Tacrolimus Mean CL: phenytoin, years) Day -9: fluconazole 100 mg PO or IV NR NR fluconazole

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First Aprepitant and Interacting Drug’s Dose Pharmacokinetic Parameters Significance and Author Study Design, Objective, and Population and Concomitant Medications Comments (Year) Without aprepitant With aprepitant - M:F =17:9 once, norfloxacin 400 mg PO q12h Tacrolimus Mean Concentrations (dose initiated (stopped at engraftment) normalized) (±SD): Adverse events Days -9 and -8: busulfan 3 mg/kg IV once Pre aprepitant therapy During aprepitant associated with daily, phenytoin 5 mg/kg IV once daily, (Day -6 to Day +1): 8.12 therapy (Day 2 to 7): aprepitant-drug granisetron 2 mg (or 3 mg if weight ± 2.31 ng/mL/mg/day 11.63 ± 5.16 interaction: NR >70kg) PO once daily, prochlorperazine ng/mL/mg/day 20 mg IV q6h, diphenhydramine 12.5 mg Post aprepitant therapy IV q6h (Day 8 until conversion Day -7: phenytoin 5 mg/kg IV once, to PO tacrolimus): fludarabine 25 mg/m2/day IV once, 11.42 ± 8.71 granisetron 2 mg (or 3 mg if weight ng/mL/mg/day >70kg) PO once, prochlorperazine 20

mg IV q6h, diphenhydramine 12.5 mg IV Tacrolimus GMR Cmax with/without aprepitant: q6h Day -6: mycophenolate mofetil 10 mg/kg IV q8h initiated, granisetron 2 mg (or 3 NR mg if weight >70kg) PO once Days -6 to -3: fludarabine mg/m2/day Tacrolimus GMR AUC with/without aprepitant: IV, granisetron 2 mg (or 3 mg if weight 0-last >70kg) PO once daily, prochlorperazine 20 mg IV q6h, diphenhydramine 12.5 mg NR IV q6h Days -3 to -1: granisetron 2 mg (or 3 mg if weight >70kg) PO once daily , prochlorperazine 20 mg IV q6h, diphenhydramine 12.5 mg IV q6h Day -1 to Day 90: Actigall 12 mg/kg/day PO in divided doses Day 0: TBI (200 cGy) , granisetron 2 mg (or 3 mg if weight >70kg) PO once, prochlorperazine 20 mg IV q6h, diphenhydramine 12.5 mg IV q6h Day 1 to 3: granisetron 2 mg (or 3 mg if weight >70kg) PO once daily Day 1 to engraftment: acyclovir 400 mg PO once daily Day 6: filgrastim 300 mcg SC initiated (continued until neutrophil count recovered)

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Shadle Study Design: double-blind, placebo-controlled Aprepitant: G1: Day 1: 125 mg PO once; Tolbutamide Geometric Mean Cmax: Clinically 23 a (2004) study Days 2 and 3: 80 mg PO once daily Baseline: 47.6 ng/mL Baseline: 43.3 ng/mL significant ?: Yes G2: placebo Day 4: 44.9 ng/mL Day 4: 42.2 ng/mL Objective: to assess effects of aprepitant on Day 8: 48.3 ng/mL Day 8: 40.9 ng/mL Funding Source: CYP2C9 and CYP3A4 over 2 weeks Tolbutamide: G1 and G2: Baseline (Day - Day 15: 47.4 ng/mL Day 15: 41.3 ng/mL Merck & Co. Inc.

7 to Day -5), Days 4, 8 and 15: 500 mg Tolbutamide Geometric Mean AUC0-∞: Population: healthy PO once Baseline: 750 ng·h/mL Baseline: 624 ng·h/mL Confounding b - N: 24 Day 4: 738 ng·h/mL Day 4: 471 ng·h/mL factors : none - Mean age: Concomitant Medications: G1 and G2: Day 8: 722ng·h/mL Day 8: 432 ng·h/mL reported o G1: 29 years (range: 18-40 Baseline (Days -7 to Day -5), Days 4, 8 Day 15: 778 ng·h/mL Day 15: 549 ng·h/mL years) and 15: midazolam 2 mg IV once Adverse events Tolbutamide Median t1/2: o G2: 29 years (range: 21-44 Baseline: 10.2 h Baseline: 8.2 h associated with years) Day 4: 10.3 h Day 4: 6.0 h aprepitant-drug - M:F = Day 8: 9.6 h Day 8: 6.0 h interaction: none o G1: 9:3 Day 15: 9.6 h Day 15: 7.3 h observed/reported o G2: 8:4 Tolbutamide Geometric Mean CL: NR NR

Tolbutamide GMR Cmax with/without aprepitant: Day 4: 1.03 (90% CI: 0.91-1.16) Day 8: 0.93 (90% CI: 0.83-1.05) Day 15: 0.96 (90% CI: 0.85-1.08)

Tolbutamide GMR AUC0-∞ with/without aprepitant: Day 4: 0.77 (90% CI: 0.67-0.88) Day 8: 0.72 (90% CI: 0.63-0.82) Day 15: 0.85 (90% CI: 0.74-0.97)

Ngo Study Design: randomized, double-blind, Aprepitant: G1: 40 mg PO once Tolbutamide Geometric Mean Cmax (CV%): Clinically 30 a (2009) placebo-controlled, parallel-group study G2: placebo Day 2: 51.61 µg/mL Day 2: 52.54 µg/mL significant ?: No (9.5) (16.3) Objective: to evaluate the effect of aprepitant Tolbutamide: G1 and G2: Day -7 to Day - Day 4: 51.08 µg/mL Day 4: 50.62 µg/mL Funding Source: on CYP2C9 activity as measured by the PK of 5 and Days 2, 4, 8 and 15: 500 mg PO (15.3) (13.0) Merck & Co., Inc. PO tolbutamide once Day 8: 48.76µg/mL Day 8: 48.47 µg/mL (12.5) (12.0) Confounding b Population: healthy, non-smoking subjects Concomitant Medications: NR Day 15: 48.93 µg/mL Day 15: 50.95 µg/mL factors : none

- N: 24 (22 subjects completed PK (16.9) (7.6) reported

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study) Tolbutamide Geometric Mean AUC0-∞(CV%): - Mean age: Day 2: 760.30 µg·h/mL Day 2: 715.46 µg·h/mL Adverse events o G1: 27 years (range: 19-37 (38.7) (28.4) associated with years); Day 4: 669.68 µg·h /mL Day 4: 581.06 µg·h /mL aprepitant-drug o G2: 26 years (range: 19-39 (41.6) (37.2) interaction: 3 years) Day 8: 745.66 µg·h /mL Day 8: 651.62 µg·h /mL cases of headache - M:F = 14:10 (12:10 in subjects who (40.4) (31.4) believed to be completed PK study) Day 15: 777.28 µg·h Day 15: 720.20 µg·h related to study /mL (36.3) /mL (30.7) drug (not specifically stated as being attributed to drug interaction)

Tolbutamide Harmonic Mean t1/2 (±pseudo SD): Day 2: 8.0 ± 2.6 h Day 2: 7.6 ± 2.0 h Day 4: 7.5 ± 2.2 h Day 4: 6.5 ± 2.1 h Day 8: 9.0 ± 3.0 h Day 8: 8.2 ± 2.4 h Day 15:8.9 ± 2.6 h Day 15: 9.0 ± 2.2 h Tolbutamide Geometric Mean CL: NR NR d Tolbutamide GMR Cmax with/without aprepitant : Day 2: 1.02 Day 4: 0.99 Day 8: 0.99 Day 15: 1.04

Tolbutamide GMR AUC0-∞ with/without aprepitantd: Day 2:0.94 Day 4: 0.87 Day 8: 0.87 Day 15: 0.93 Aprepitant + Warfarin

Depre Study Design: double-blind, placebo- Aprepitant: Period 2: G1: Day 1: 125 mg Warfarin Geometric Mean Cmax: Clinically 31 a (2005) controlled, randomized, 2-period, parallel- PO once; Days 2 and 3: 80 mg PO once S(-) warfarin: 517 ng/mL S(-) warfarin: 512 significant ?: No group study daily R (+) warfarin: 718 ng/mL G2: placebo ng/mL R (+) warfarin: 749 Funding Source: Objective: to evaluate the effect of a 3-day oral ng/mL Merck & Co., Inc.

dose regimen of aprepitant on the steady state Warfarin: Period 1: G1 and G2: warfarin Warfarin Geometric Mean AUC0-24h: PK and PD of warfarin in healthy subjects 5 mg/day PO for 4 days followed by S(-) warfarin: 9523 S(-) warfarin: 9370 Confounding

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First Aprepitant and Interacting Drug’s Dose Pharmacokinetic Parameters Significance and Author Study Design, Objective, and Population and Concomitant Medications Comments (Year) Without aprepitant With aprepitant individualized warfarin dose to INR of ng·h/mL ng·h/mL factorsb: none Population: healthy, non-smoking subjects 1.3-1.8 for four consecutive days after R(+) warfarin: 14020 R(+) warfarin: 14547 reported - N: 25 (22 completed study) which maintenance dose was fixed for ng·h/mL ng·h/mL

- Mean age: 29 years (range: 21-45 10-12 consecutive days Warfarin Mean t1/2 : Adverse events years) Period 2: G1 and G2: Day -1 to 8: NR NR associated with - M:F = 23:2 individualized daily warfarin dose Warfarin Geometric Mean CL: aprepitant-drug NR NR interaction: none Concomitant Medications: NR Warfarin GMR C with/without aprepitant: observed/reported max S(-) warfarin: 0.96 (90%CI: 0.90-1.04) R(+) warfarin: 1.05 (90%CI: 0.98-1.12)

Warfarin GMR AUC0-24h with/without aprepitant: S(-) warfarin: 0.96 (90%CI: 0.92-1.01) R(+) warfarin: 1.04 (90%CI: 1.00-1.08) P-GP Interaction Suspected Aprepitant + Digoxin

Feuring Study Design: double-blind, placebo- Aprepitant: Period 2: G1: Day 7: 125 mg Digoxin Geometric Mean Cmax: Clinically 32 a (2003) controlled, randomized, two-period crossover PO once, Days 8-11: 80 mg PO once Day 7: 1.20 ng/mL Day 7: 1.25 ng/mL significant ?: No study with a 14 day washout period daily Day 11: 1.15 ng/mL Day 11: 1.17 ng/mL

G2: placebo Digoxin Geometric Mean AUC0-24h: Funding Source: Objective: to determine if the steady-state Day 7: 10.6 ng∙h/mL Day 7: 10.5 ng∙h/mL NR, authors plasma concentration or urinary excretion of Digoxin: Period 1 and 2: Day 1 to Day 13: Day 11: 10.6 ng∙h/mL Day 11: 9.9 ng∙h/mL associated with digoxin after oral digoxin administration were 0.25 mg PO once daily Merck & Co., Inc. Digoxin Mean t1/2: altered by a 5-day oral regimen of aprepitant in healthy subjects NR NR Concomitant Medications: none Confounding Digoxin Geometric Mean Urinary CL: factorsb: none Population: healthy, non-smoking subjects Day 7: 156 mL/min Day 7: 143 mL/min reported - N: 12 (11 subjects completed PK Day 11: 150 mL/min Day 11: 159 mL/min

analysis) Digoxin GMR C with/without aprepitant: max Adverse events - Mean age: 29.6 years (range: 22-45 Day 7: 1.04 (90%CI: 0.89-1.23) associated with years) Day 11: 1.02 (90%CI: 0.92-1.14) aprepitant-drug - M:F = 6:6 Digoxin GMR AUC0-24h with/without aprepitant: interaction: none Day 7: 0.99 (90%CI: 0.91-1.09) observed/reported Day 11: 0.93 (90%CI: 0.83-1.05) Pharmacokinetic Drug Interaction Suspected, Exact Mechanism Unknown Aprepitant + Paroxetine

Ball Study Design: 6-week, double-blind, Aprepitant(A): 200 mg PO daily Paroxetine Mean Cmax: Clinically 33 a (2014) randomized, comparator-controlled, parallel- Decreased 20% Significant ? UTD NR group, phase 2 study Paroxetine(P): 20 mg PO daily (p=0.020)

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Paroxetine Mean AUC0-24h: Funding Source: Objective: to determine whether concomitant Concomitant Medications: NR Decreased 25% Merck & Co., Inc. NR aprepitant and paroxetine use would provide (p=0.012) Confounding greater antidepressant efficacy (primary Paroxetine Mean t1/2: factorsb: none outcome: Hamilton Depression Rating Scale NR NR reported (HAMD-17) score); secondary objective was to Paroxetine Mean CL:

examine safety and tolerability of combination NR NR Adverse events Paroxetine GMR C with/without aprepitant: Population: major depressive disorder max associated with NR - N: 236 aprepitant-drug - Median age: 38.9 years (range: 18-65 Paroxetine GMR AUC0-24h with/without aprepitant: interaction: years) NR therapy - M:F = 74:162 *Results for primary efficacy outcome (mean discontinued change in HAMD-17 score from baseline to 6 higher in A+P group weeks) (±SD): was higher (15.2% - Paroxetine: -11.7 ± 7.2 (A+P) vs 6.4% (P) vs - Paroxetine + aprepitant: -11.0 ± 7 10.1% (A) (no p- - Estimated difference between treatments: value reported); 0.6 (95%CI: -1.6-2.8), p=0.567 Dry mouth: - A+P: 25.3% - A: 10.1% - P: 14.1% Tremor: - A+P: 13.9% - A: 1.3% - P: 5.1% Pharmacokinetic Drug Interaction Not Suspected Aprepitant + Alcohol

TeBeek Study Design: double-blind, randomized, Aprepitant: Days 4-10: 160 mg PO once Alcohol Mean Cmax: Clinically 34 a (2013) placebo—and active comparator-controlled, daily NR NR Significant ? UTD

triple-dummy, four treatment, two-period Alcohol Mean AUC0-24h: crossover study 5% Ethanol in 5% glucose solution: Day NR NR Funding Source: 10: IV over 4 hours at a rate to achieve a Merck & Co., Inc. Alcohol Mean t1/2: Objective: to compare effects of co- blood ethanol concentration of 0.65 g/L NR NR administration of aprepitant and alcohol with Confounding Alcohol Mean CL: b those of alcohol and aprepitant alone Concomitant Medications: Day 1: factors : NR NR

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First Aprepitant and Interacting Drug’s Dose Pharmacokinetic Parameters Significance and Author Study Design, Objective, and Population and Concomitant Medications Comments (Year) Without aprepitant With aprepitant amitriptyline 50 mg PO once (active Breath alcohol concentration (g/L): Amitriptyline (long Population: healthy subjects comparator), Days 2 and 3: placebo (5% Did not differ significantly in presence of half-life) - N: 17 glucose) IV aprepitant

- Mean age: 27 years (range: 18-53 Alcohol GMR Cmax with/without aprepitant: Adverse events years) NR associated with - M:F = 9:8 aprepitant-drug Alcohol GMR AUC0-24h with/without aprepitant: NR interaction: longer reaction time for immediate pattern recognition (p=0.043) and adaptive tracking at 7.5 h (p=0.043). Authors concluded that these were not clinically significant since effects were not consistently observed. There was no statistically significant difference in any of the other cognitive tests. PO, by mouth; IV, intravenously; N, number of study subjects; M, male; F, female; GMR, geometric mean ratio; NR, not reported; PK, pharmacokinetic; inf, infinity; CV%, coefficient of variation; h, hour; TDM, therapeutic drug monitoring; eoi, end of infusion a Clinical significance is defined by review authors as the geometric mean ratio of with aprepitant/without aprepitant for Cmax or AUC value >1.25 or <0.80 bConfounding factors may include other medications that a study subject may have received that would alter the pharmacokinetic disposition of the interacting drug or anything that was mentioned in the study paper that would impact the pharmacokinetic disposition of the interacting drug cSystematic review study investigator calculated arithmetic mean ratio (GMR not provided by author in publication) dSystematic review study investigator calculated GMR

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Supplementary Table B8. Drug interaction studies evaluating potential adverse events resulting from potential drug interactions between aprepitant or fosaprepitant and an antineoplastic agent Aprepitant and Interacting First Author Study Design, Objective, and Significance and Drug’s Dose + Adverse Events (Year) Population Comments Concomitant Medications Fosaprepitant + Anthracycline Prospective Observational Studies Kameda (2014) Study design: prospective observational cohort Fosaprepitant: Day 1: 150 mg IV Vascular Pain: 30% (6/20) Funding source: NR [Japanese]35 study once Confounding Objective: to assess whether dexamethasone is Epirubicin: Day 1: 100 mg/m2 IV factorsa: none an effective agent for relieving the vascular pain once reported induced by fosaprepitant. Concomitant medications: Population: Japanese breast cancer patients All patients: - N: 20 (only characteristics of 6 patients Day 1: cyclophosphamide 500 experiencing vascular-pain presented) mg IV once, Fluorouracil 500 mg - Median age: 48.5 years (range: 23-67 IV once years) Patients experiencing vascular - M:F = NR pain: dexamethasone 3.3 mg IV Retrospective Observational Studies Sato (2014)36 Study Design: retrospective review Fosaprepitant: 150 mg IV once Without fosaprepitant With fosaprepitant Funding source: infused over 20 minutes Infusion site reaction per patient training expenses of Objective: to determine the incidence of infusion- 67% (16/24) Nagoya City West 16% (5/32) site reactions with single-dose IV fosaprepitant in Chemotherapy (one of three P=0.0002 Medical Center patients treated with an anthracycline regimens all administered Infusion site reaction requiring treatment per peripherally): patient Confounding 2 a Population: receiving fosaprepitant through 1) FEC: epirubicin 100 mg/m 50% (12/24) factors : varying 3.1% (1/32) peripheral IV line IV, cyclophosphamide 500 P<0.0001 chemotherapy - N: 56 (24 with fosaprepitant (61 mg/m2 IV, 5-fluorouracil regimens 2 Infusion site reaction per injection injections); 32 without fosaprepitant 500 mg/m IV 34% (21/61) 2 8.2% (8/98) (98 injections)) 2) AC: doxorubicin 60 mg/m P<0.0001 - Median age: 50 years (range: 31-85 IV, cyclophosphamide 600 2 Infusion site reaction requiring treatment per years) mg/m IV injection - M:F = 7:49 3) (R-)CHOP: vincristine 1.4 28% (17/61) mg/m2 IV, doxorubicin 50 1.0% (1/98) P<0.0001 mg/m2 IV, Pain cyclophosphamide 750 mg/m2 IV 6% (6/98) 23% (14/61) Erythema Concomitant medications (all 1% (1/98) 16% (10/61)

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Aprepitant and Interacting First Author Study Design, Objective, and Significance and Drug’s Dose + Adverse Events (Year) Population Comments Concomitant Medications administered peripherally): Swelling - FEC and AC: palonosetron NR 10% (6/61) 0.75mg IV once + Discontinuation of chemotherapy injections dexamethasone 9.9 mg IV NR 3% (2/61) - (R)-CHOP: granisetron 3 mg IV once Lundberg Study Design: retrospective review Fosaprepitant: 150 mg/100 mL Infusion-site reactions: 15% (50/333; 95% CI: 11.4- Funding source: NR (2014)37 IV once infused over 20 minutes 19.3) Objective: to investigate the incidence of - 50 reactions occurred in 43 patients Confounding infusion-site reactions with a single-dose IV Vesicant chemotherapy: NR factorsa: specific fosaprepitant when given through peripheral line Concurrent vesicant chemotherapy (e.g. chemotherapy preceding chemotherapy anthracycline) as a risk factor for infusion-site regimens not reaction: reported, 45 Population: patients administered fosaprepitant - Multivariable analysis: not statistically patients (22 in IV through a peripheral vein significant reaction group) - N: 150 (333 doses of fosaprepitant) - Univariate analysis: OR 4.15 (95% CI: received vesicant - Median age: 2.21-7.78); p<0.001 chemotherapy o Reaction group: 54 years (interquartile range: 49-62 Concurrent non-vesicant chemotherapy as a risk years) factor for infusion-site reaction: o No reaction group: 59 years - Univariate analysis: OR 1.38 (95% CI: (interquartile range: 51-67 0.16-11.8); p=0.767 years) - M:F = 77:73 Authors’ conclusions: location of IV line, and simultaneous maintenance IV fluid rate of <100 mL/h factors also risk factors for infusion-site reactions Mogi (2014)38 Study Design: retrospective review Fosaprepitant: NR 16.3% (13/80) phlebitis (CTCAE v.4 grade 1) Funding source: NR [abstract] Phlebitis Objective: to determine incidence of phlebitis in Chemotherapy: NR Confounding Without fosaprepitant With fosaprepitant colorectal cancer patients factorsa: UTD

Concomitant medications: oral 92.3% Population: colorectal cancer treated with oral aprepitant substituted for IV 52.2% P<0.05 fluoropyrimidine + IV oxaliplatin or IV irinotecan fosaprepitant in 6 patients with Oral aprepitant given through peripheral vein phlebitis substituted for IV - N: 80 fosaprepitant and no - Median age: NR further phlebitis - M:F = NR observed

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Aprepitant and Interacting First Author Study Design, Objective, and Significance and Drug’s Dose + Adverse Events (Year) Population Comments Concomitant Medications 39 Fujii (2015) Study Design: retrospective study G1: aprepitant: NR Infusion Site AE (e.g. infusion site reactions or skin Funding Source: NR induration), CTCAE grade 1 or 2 Objective: to compare infusion site adverse G2: fosaprepitant: NR Cisplatin Anthracycline Confounding a events associated with fosaprepitant (vs Fosaprepitant: 18.6% Fosaprepitant: 54.6% factors : Cisplatin: NR aprepitant) differs between patients receiving anthracycline group (8/43) 42/77 cisplatin vs anthracyclines Anthracycline(doxorubicin or Aprepitant: 16.1% Aprepitant: 9.5% only composed of epirubicin): NR (5/31) (11/116) female breast Population: patients administered anthracycline P=0.783 P<0.001 cancer patients, or cisplatin-based regimens not through a central Concomitant medications OR (fosaprepitant, yes OR (fosaprepitant, yes cyclophosphamide line combined with cisplatin: S-1 or vs no), adjusted*: 0.78 vs no), adjusted*: 12.95 - N: 267 (120 fosaprepitant, 147 Pemetrexed or gemcitabine or 5- (95% CI: 0.20-3.05), (95% CI: 5.74-29.2), aprepitant) fluoruracil or vinorelbine or p=0.717 p<0.001 - Mean age: 54.3 years (Fosaprepitant: etoposide or irinotecan or 55.1 ± 12.8 years, aprepitant: 53.5 ± docetaxel or capecitabine *adjusted for age, 11.8 years) (range: NR) Concomitant medications gender, BMI, cancer - M:F = 43:224; (fosaprepitant: 23:97; combined with anthracycline: type and number of aprepitant: 20:127) cyclophosphamide ± 5- prior regimen flurouracil Hegerova Study design: retrospective review Fosaprepitant: 150 mg IV once Infusion site adverse event Funding source: (2015)40 Platinum, N (%) AC, N (%) United States Objective: (1) to assess whether platinum-based Platinum-based chemotherapy: National Institutes chemotherapy regimens are associated with 7.4% (6/81) [3% 34% (33/99) [12% NR of Health Grant –CA increased infusion site adverse events when used swelling, 3% swelling, 4% 124477 with fosaprepitant antiemetic therapy and (2) to extravasation, 3% extravasation, 5% Anthracycline-cyclophosphamide compare the venous toxicity indices of those who phlebitis] phlebitis] chemotherapy: NR Confounding had received anthracycline-cyclophosphamide a factors : primary (AC) in a previous study to patients receiving All occurred in patients When stratified by Concomitant medications: NR cancer site platinum-based chemotherapy with peripheral venous regimen and adjusted

access for gender, Population: patients administered platinum- fosaprepitant was based chemotherapy that did not contain an associated with anthracycline increased risk of ISAE in - N: 81 AC group - Mean age: 56.4 ± 13.2 years (range: 22- OR 8.1 (95% CI: 2.0- 77 years) 31.9) - M:F = 50:31 p<0.001 (compared to Population from previous study (comparator): platinum group) patients administered anthracycline- cyclophosphamide chemotherapy

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Aprepitant and Interacting First Author Study Design, Objective, and Significance and Drug’s Dose + Adverse Events (Year) Population Comments Concomitant Medications - N: 99 - Mean age: 53.3 ± 9.7 years (range: 31- 74 years) - M:F = 2:97

Tsuda (2016)41 Study design: retrospective review Fosaprepitant: NR Infusion site reactions of any grade experienced at Funding source: NR least once Objective: to compare the incidence of infusion Aprepitant: NR Aprepitant Fosaprepitant Confounding a site reactions 3 months prior to and 3 months 42% (26/62) 96% (36/38) factors : following switching change from aprepitant to Anthracycline-based P<0.001 cyclophosphamide fosaprepitant chemotherapy: - EC: Day 1 every 3 weeks: Owing to infusion site 2 Population: chemo-naïve breast cancer patients epirubicin 90 mg/m IV, reactions, fosaprepitant receiving anthracycline-containing chemotherapy cyclophosphamide 600 was discontinued in 19 2 - N:102 (100 included in analysis, 2 mg/m IV patients excluded for switching from - FEC: Day 1 every 3 weeks 2 fosaprepitant to aprepitant during epirubicin 100 mg/m IV, Observed infusion site chemotherapy, in spite of absence of cyclophosphamide 500 adverse effects: pain, 2 infusion site adverse events) mg/m IV, fluorouracil swelling, erythema, 2 - Median age: 500 mg/m IV venous induration, local o Aprepitant: 52 years (range: 30- scarring, difficulty 75 years) Concomitant medications: flexing, heat sensation o Fosaprepitant: 47 years (range: granisetron 1 mg, ranitidine 50 and phlebitis. 31-66 years) mg and - M:F = NR Day 1: dexamethasone 6.6 mg IV Days 2 and 3: dexamethasone 8 mg PO

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Aprepitant and Interacting First Author Study Design, Objective, and Significance and Drug’s Dose + Adverse Events (Year) Population Comments Concomitant Medications Aprepitant + Bexarotene Case Report Ruellan Study Design: case report Aprepitant: 80 mg PO once daily November 2011: generalized asthenia, anorexia Funding Source: NR (2012)42 (initiated September 2011) and aphagia, leading to 15 kg weight loss in 3 [abstract] Population: patient with Erythrodermic Sezary Bexarotene: 300 mg/m2 PO once weeks, Confounding syndrome daily (initiated November 2009) severe dehydration associated with hypernatremia factorsa: none - N: 1 Concomitant medications: (185mmol/L) and acute renal insufficiency reported - Age: 65 years alpha2a interferon 3 million IU 3 December 2011: death - M:F = 1:0 times per week (initiated DIPS Score: -2 November 2009) Date of discontinuation of aprepitant: NR

Aprepitant + Erlotinib Case Report Sassier Study Design: case report Aprepitant: NR Gastrointestinal Toxicity: Funding source: NR (2016)43 Chemotherapy Cycle 1: Grade 2 nausea and Population: non-small cell lung cancer and brain Erlotinib: 150 mg /day (route NR) vomiting beginning 2 days after start of Confounding metastases chemotherapy and asthenia lasting 10 days Factorsa: verapamil, - N: 1 Concomitant Medications: Chemotherapy Cycle 2: Grade 3 vomiting 2 days prednisolone - Age: 56 years cisplatin 90 mg (route NR), after receiving chemotherapy - M:F = 0:1 pemetrexed 600 mg (route NR), Chemotherapy Cycle 3: Grade 4 vomiting and DIPS Score: 3 prednisolone, oxycodone, diarrhea 14 days after receiving chemotherapy verapamil associated with renal insufficiency; patient had rapid improvement during hospitalization Aprepitant + Ifosfamide Retrospective Observational Studies Howell Study Design: retrospective cohort study Aprepitant: Day 1: 125 mg PO 18% (8/45) ifosfamide-induced neurotoxicity Funding Source: NR (2008)44 once, Days 2 and 3: 80 mg PO - 75% (6/8) received aprepitant Confounding Objective: to determine whether the addition of once daily - RR (with aprepitant vs without factorsa: albumin aprepitant to mesna, doxorubicin and ifosfamide MAI: ifosfamide 3.75 g/m2/day aprepitant): levels lower and (MAI) may increase the incidence of neurotoxicity IV daily for 2 days, doxorubicin 2.6 (95% CI: 0.47-26.6) bilirubin levels 30 mg/m2/day IV push for 2 higher in patients Population: sarcoma days, and mesna 400 mg/m2 with neurotoxicity, - N: 45 bolus with a 2400 mg/m2/day baseline delirium - Mean age: 53 years (aprepitant group), continuous infusion thereafter score, concomitant 48 years (no aprepitant group) (range: OR CNS depressant NR) Ifosfamide 2.5g/m2/day IV daily medications - M:F =23:22 for 4 days, doxorubicin 25 mg/m2/day IV continuous

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Aprepitant and Interacting First Author Study Design, Objective, and Significance and Drug’s Dose + Adverse Events (Year) Population Comments Concomitant Medications infusion for 3 days, and mesna 500 mg/m2 IV bolus with a 1500 mg/m2/day IV continuous infusion thereafter Concomitant medications: lorazepam (prn), opioid (prn), dolasetron, prochlorperazine, dexamethasone Ho (2010)45 Study Design: retrospective case-control study Aprepitant: NR Ifosfamide-induced neurotoxicity: 12% (7/54) Funding Source: NR [letter to editor] Objective: to determine if there is an increased MAI (38 patients): ifosfamide 2.5 Aprepitant administration: Confounding rate of ifosfamide-induced neurotoxicity in g/m2/day IV daily for 4 days, - Cases: 47% (4/7) factorsa: albumin patients who received aprepitant vs patients who doxorubicin 25 mg/m2/day IV - Controls: 59% (28/47) levels lower in did not continuous infusion x 3 days, and - OR = 0.91 (CI: 0.18-4.51), p=1 patients with mesna 2500 mg/m2 continuous neurotoxicity Population: sarcoma patients infusion x 4 days - N: 54 (7 cases, 47 controls) - Mean age (±SD): cases: 48 ± 9.6 years, High-dose ifosfamide containing controls: 44.8 ± 11.7 years (range: NR) regimens (16 patients) combined - M:F = 38:16 or alternating with cyclophosphamide, etoposide and vincristine Stern (2015)46 Study design: retrospective study Aprepitant: NR Ifosfamide-related encephalopathy: 4.2% (8/187); Funding source: NR [abstract] None received aprepitant. Objective: to assess risk factors for ifosfamide- Ifsofamide: NR Confounding related encephalopathy after the 2 first cycles of factorsa: UTD ifosfamide-based chemotherapy

Population: patients treated with ifosfamide - N: 187 (8 received aprepitant) - Median age: 27 years (range 0-78 years) - M:F = NR Chenaf Study design: retrospective review of Aprepitant: NR Neurotoxicity, patients receiving aprepitant: Funding source: NR (2015)47 pharmacovigilence database - Brand name: 10% [abstract] Ifosfamide: NR - Generic: 27% Confounding Objective: to compare the features of factorsa: UTD neurotoxicity cases between patients using Concomitant Medications: NR brand-name vs generic ifosfamide

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Aprepitant and Interacting First Author Study Design, Objective, and Significance and Drug’s Dose + Adverse Events (Year) Population Comments Concomitant Medications

Population: patients receiving ifosfamide and experiencing neurotoxicity - N: 178 (206 cases: 178 brand name, 28 generic) - Median age: 49 years (brand name) and 14 years (generic) - M:F = 72:106 Gupta (2016)48 Study design: retrospective chart review Fosaprepitant: NR Ifosfamide-induced encephalopathy: Funding source: NR [abstract] Objective: to examine the relationship between - Fosaprepitant: 6.6% (3/45) the use of fosaprepitant and development of Ifsofamide: NR - No fosaprepitant: 11.1% (4/35) Confounding ifosfamide-induced encephalopathy - P=0.69 factorsa: albumin, Population: patients receiving ifosfamide pelvic disease, poor - N: 81 (1 lost to follow-up) ECOG performance - Median age: NR (range: NR) status, higher - M:F = NR baseline SCr Mahe (2016)49 Study design: retrospective study Aprepitant: NR No significant difference between neurotoxicity Funding source: NR [abstract] frequency before and after aprepitant use Objective: to compare proportion of ifosfamide- Ifosfamide: NR (p=0.11) Confounding induced neurotoxicity cases before and after factorsa: different generic ifosfamide use or aprepitant use ifosfamide formulations (brand Population: patients treated with at least one vs generic) ifosfamide course between January 2003 and October 2014 - N: 213 (21 patients had an episode of neurotoxicity) - Median age: 13 years (1-20) of those who experienced neurotoxicity - M:F=12:9 of those who experienced neurotoxicity Case Reports Jarkowski Study Design: case report Aprepitant: Day 1: 125 mg PO, Ifosfamide-induced neurotoxicity Funding Source: NR (2008)50 Day 2 and 3: 80 mg PO (encephalopathy): visual and auditory Population: malignant peripheral nerve sheath (beginning cycle 6) hallucinations, sleepiness, confusion and delirium Confounding tumor lasting less than 24 hours (beginning Day 3 of cycle factorsa: none 2 - N: 1 Ifosfamide: Days 1-3: 3 g/m IV 6) reported/UTD - Age: 24 years daily

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Aprepitant and Interacting First Author Study Design, Objective, and Significance and Drug’s Dose + Adverse Events (Year) Population Comments Concomitant Medications - M:F = 1:0 Concomitant Medications: Patient experienced no neurotoxicity it prior 5 DIPS Score: 4 Day 1: dexamethasone 12 mg PO cycles Day 1-3: etoposide 100 mg/m2 IV Day 3: carboplatin 635 mg/m2 IV When ifosfamide + aprepitant given along with Days 2-4: 8 mg PO methylene blue cycle 7 no neurological toxicity Starting day 1: ondansetron 8 reported mg IV q8h (duration unclear) McDonnell Study Design: case report Aprepitant: NR Morning of day 2 lethargic, chemotherapy held Funding source: NR (2012)51 *interaction between aprepitant and ifosfamide Population: non-Hodgkin lymphoma with Ifosfamide: NR not suggested as risk factor Confounding ifosfamide-induced encephalopathy factorsa: paroxetine, - N: 1 Concurrent medications: After administration methylene blue: mydriasis, bupropion, - Age: 66 years carboplatin, etoposide, occasional jerks, hyperreflexia, increasingly dexamethasone - M:F = 0:1 paroxetine, bupropion, unresponsive, tachypneic, tachycardic, and dexamethasone, methylene blue acidotic (aprepitant, paroxetine, bupropion and DIPS Score: 3 methylene discontinued) – serotonin syndrome due to paroxetine + methylene blue suspected Shindorf Study Design: case reports Aprepitant: Day 1: 125 mg PO Ifosfamide-induced neurotoxicity Funding Source: NR (2013)52 once, Days 2 and 3: 80 mg PO (encephalopathy) suspected in both cases, Population: once daily presented as: Confounding - C1: ovarian malignant mixed - C1: coma lasting 24 hours beginning on factorsa: UTD mesodermal tumor (MMMT) Ifosfamide: day 3 - C2: uterine MMMT C1: Days 1-4: 1 g/m2 IV daily - C2: auditory and visual hallucinations DIPS Score: C1: 3, - N: 2 C2: Days 1-4: 1.5 g/m2 IV daily and labile emotions lasting less than 24 C2: 3 - Age: C1: 67 years, C2: 41 years hours beginning on day 3 - M:F = 0:2 Concomitant Medications: C1: Days 1-4: cisplatin 20 mg/m2 IV + mesna, Day 1: dexamethasone 10 mg Day 1, Days 2-3: 8 mg C2: Days 1-4: cisplatin 20 mg/m2 IV + mesna, Day 1: dexamethasone 10 mg Day 1, Days 2-4: 8 mg Sejourne Study Design: case reports Aprepitant: Ifosfamide-induced neurotoxicity Funding source: NR (2014)53 C1: Day 1: 125 mg PO once, Days (encephalopathy) suspected in both cases, Population: 2 and 3: 80 mg PO once daily presented as: Confounding - C1: uterine leiomyosarcoma C2: 80 mg PO once Daily x 5 days - C1: obnubilation, awareness troubles, factorsa:

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Aprepitant and Interacting First Author Study Design, Objective, and Significance and Drug’s Dose + Adverse Events (Year) Population Comments Concomitant Medications - C2: pleiomorphic rhabdomyosarcoma and death despite methylene blue -C1: oxycodone, - N: 2 Ifosfamide: administration chlorpromazine - Age: C1: 39 years, C2: 75 years C1: 5 g/m2/day IV (duration NR) - C2: 8 days after cycle 3 or ifosfamide + -C2: sepsis, lung - M:F = 0:2 C2: 2 g/m2/day IV for 5 days q3w aprepitant: vigilance disorders and infection, for 3 cycles confusion (Glasgow coma score 13), and pancytopenia, renal death despite methylene blue insufficiency Concomitant Medications: administration C1: steroids (given with DIPS Score: C1: 2, aprepitant), oxycodone and C2: 2 chlorpromazine (discontinued at onset of neurological symptoms) C2: steroids Barthelemi Study design: case series Aprepitant: NR Ifosfamide-induced encephalopathy characterized Funding source: NR (2015)54 by general neurological symptoms in all 10 [abstract] Objective: to report neurologic symptoms, Ifosfamide: NR patients (i.e. impaired consciousness, confusion) Confounding treatments and consequences of methylene blue factorsa: UTD treatment Concomitant Medications: NR 1/10 patients received aprepitant

Population: patients experiencing ifosfamide- induced encephalopathy - N: 10 - Median age: NR; 8 children aged 2-15 years, 2 adults aged 51 and 80 years - M:F = NR Sunela Study design: case reports Aprepitant: NR Ifosfamide-induced encephalopathy: Funding source: NR (2016)55 - C1: patient presented with confusion Population: Ifosfamide: beginning day 2 of Cycle 5 of Confounding - C1: osteosarcoma patient with previous C1: 3000 mg/m2/day IV chemotherapy (received ifosfamide two factorsa: -C1: history of breast cancer C2: 2000 mg/m2/day IV for 3 times previously with no dexamethasone, - C2: metastatic sarcoma days encephalopathy) lorazepam, - N: 2 - C2: confused, disoriented, some hypokalemia - Age: C1: 59 years, C2: 65 years Concomitant Medications: agitation and aphasic on Day 3 of -C2: - M:F = 1:1 C1: palonosetron, ifosfamide therapy (confusion lasted for dexamethasone, dexamethasone, and lorazepam 5 days despite methylene blue therapy). SSRI and C2: dexamethasone, granisetron Aprepitant was not given in the next carbamazepine, chemotherapy cycle, but patient albumin, experienced confusion again. hypokalemia

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Aprepitant and Interacting First Author Study Design, Objective, and Significance and Drug’s Dose + Adverse Events (Year) Population Comments Concomitant Medications DIPS Score: C1: 2, C2: 0 PO, by mouth; IV, intravenously; N, number of study subjects; M, male; F, female; NR, not reported; OR, odds ratio; RR, relative risk aConfounding factors may include other medications that a study subject may have received that would alter the pharmacokinetic disposition of the interacting drug or anything that was mentioned in the study paper that would impact the pharmacokinetic disposition of the interacting drug

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Supplementary Table B9. Drug interaction studies evaluating potential adverse events resulting from potential drug interactions between aprepitant or fosaprepitant and a non-antineoplastic agent Aprepitant and Interacting First Author Significance and Study Design, Objective, and Population Drug’s Dose + Concomitant Adverse Events (Year) Comments Medications Aprepitant + Oxycodone Walsh (2013)56 Study Design: 6-week, randomized, double- Aprepitant: Subject-rated Measures Funding Source: blind, double-dummy, within-subject, placebo- A1: 40 mg PO once Aprepitant significantly enhanced response to National Institute on controlled, crossover design A2: 2000 mg PO once oxycodone most particularly at higher oxycodone Drug Abuse grant, A3: placebo doses. Clinical and Objective: examine the effects of aprepitant on Translational the subjective and physiologic response to a Oxycodone: Assessment of “high”: aprepitant increased effect Science Award and prototypic mu opioid agonist in individuals with O1: 20 mg/70 kg PO for PO (P=0.039) and inhaled oxycodone (p=0.007) Merck & Co., Inc. histories of prescription opioid abuse to test if O2: 40 mg/70 kg PO Street value estimate: aprepitant increased street neurokinin-1 receptor antagonists diminish the O3: 15 mg/70 kg inhalation Confounding value estimates for PO (p=0.023) and inhaled a effects of opioids related to their abuse O4: 30 mg/70 kg inhalation Factors : NR oxycodone (p=0.004) potential O5: placebo

Opioid Agonist Adjective Scale: aprepitant increased Population: illicit opioid users (not physically Concomitant Medications: NR scores in response to PO (p=0.008) and intranasal dependent) oxycodone (p=0.008) - N: 8 - Mean Age: 32.3 years Observer-rated Measures - M:F = 6:2 Of all measures, only “drunken” ratings increased with aprepitant and PO or intranasal oxycodone.

Opioid Agonist Adjective Scale: aprepitant did not increase scores in response to PO or intranasal oxycodone.

Physiological Outcomes With aprepitant:  Increased end tidal carbon dioxide with PO oxycodone (p=0.028) and intranasal oxycodone (p=0.001)  Oxygen saturation: no significant interaction  Lower respiratory rate: oral (p<0.025) and intranasal oxycodone (p=0.005)  Time-dependent miosis: no significant interaction  Heart rate: decreased decline with PO

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Aprepitant and Interacting First Author Significance and Study Design, Objective, and Population Drug’s Dose + Concomitant Adverse Events (Year) Comments Medications oxycodone (p=0.037)  Blood pressure: no significant interaction

Psychomotor Measures No significant drug interaction effects with aprepitant for flicker fusion test, Maddox Wing Test and digital symbol substitution task response trials Aprepitant + Methadone Jones (2013)57 Study design: outpatient, placebo-controlled, Aprepitant: Days 1-3 and 8-10: Aprepitant: Funding source: NYU double-blind crossover study with a washout 80 mg PO or placebo pre- - Did not affect participants’ desire to use Langone Medical period of at least 5 days methadone methadone (p=0.09) Center Seed Grant - Did not decrease opioid craving (p=0.10) Objective: to examine the ability of aprepitant Methadone: NR, patient-specific - Did not increase participants’ ratings of Confounding to alter the effects of methadone and the once daily dosing (mean daily methadone “Liking” (p=-0.08) Factorsa: methadone withdrawal symptoms induced by brief dose 80.9 ± 9 mg, ranging from - Did not affect Subjective Opioid dosing methadone discontinuation 28-130 mg PO) Withdrawal Scale (COWS) scores (p=0.10) - Days 3 and 10: - Did not affect Clinical Opioid Withdrawal Population: methadone-maintained patients methadone dose time Scale (SOWS) scores with opioid abuse and dependence prolonged by 7 hours - N: 20 (15 patients completed study) (i.e. 7 hours after No adverse events determined as being “definitely” - Mean Age: 47.3 years (range: 31-59 years) aprepitant dose) related to aprepitant. - M:F = 11:4 of those who completed study Aprepitant + SSRI Mir (2012)58 Study design: retrospective case-control study Aprepitant: Day 1: 125 mg PO Rates of grade ≥1 vomiting in patients receiving Funding source: NR, once, Days 2-5: 80 mg PO once aprepitant: author affiliations Objective: to determine whether cancer daily - SSRI/SNRI vs. no SSRI/SNRI: 52.9% vs. 29.4% with Roche, Pfizer patients receiving SSRI or SNRI were at higher (p=0.29) and Merck & Co., risk of acute vomiting after the administration SSRI/SNRI: NR Inc. of highly emetogenic chemotherapy, despite Rates of grade ≥2 vomiting in patients receiving the use of prophylactic antiemetic agents Concomitant Medications: Days aprepitant: Confounding 1-3: etoposide 120 mg/m2 IV, - SSRI/SNRI vs. no SSRI/SNRI: 41.2% vs. 5.9% factorsa: varying Population: chemotherapy-naïve patients cisplatin 30 mg/m2 IV every 21 (p=0.04) SSRI/SNRIs studied, receiving etoposide and platinum days, methylprednisolone 80 mg corticosteroid use chemotherapy with concomitant treatment of IV, ondansetron 8 mg PO/IV, SSRI or SNRI (cases) or no no SSRI/SNRI therapy Days 4-5: prednisolone 80 mg PO (controls) daily metoclopramide or - N: 44 (22 cases) alizapride IV or PO PRN - Median Age: 59 years (34-78 years) - M:F = 18:26

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Aprepitant and Interacting First Author Significance and Study Design, Objective, and Population Drug’s Dose + Concomitant Adverse Events (Year) Comments Medications Aprepitant + Warfarin Yano (2011)59 Study design: Case reports C1: C1: Funding Source: NR Aprepitant: Day 1: 125 mg PO Objective: to report 2 cases of a probable once, Days 2 and 3: 80 mg PO INR prior to chemotherapy: 2.19-2.58 Confounding interaction between warfarin and cisplatin a once daily INR Day 3 post-cisplatin: 3.43 factors : Cases: chemotherapy, - C1: ovarian malignancy + Warfarin: 3.25 mg/day PO (INR Elevated INR seen for future cycles of dexamethasone, disseminated intravascular target: 2-2.5) chemotherapy as well changes in disease coagulation state, appetite loss - C2: peritoneal recurrence and liver Concomitant Medications: Day 1, 2 metastasis of uterine cervical 8, 15: irinotecan 60 mg/m , DIPS Score: C1: 7, adenocarcinoma granisetron 3 mg, Day 1: cisplatin C2: 7 2 - N: 2 60 mg/m q4 weeks, - Age: C1: 50 years, C2: 43 years dexamethasone 13.2 mg, Days 2, - M:F=0:2 3, 8 and 15: dexamethasone 6.6 C2: mg, aspirin 100 mg PO daily During Cycle 2 of chemotherapy: C2: INR prior to chemotherapy: 1.17-1.22 Aprepitant: Day 1, 8 and 15: 125 INR Day 3 post-cisplatin: increased from 1.3 to 1.77 mg PO once, Days 2-5, 9, 10, 16 INR Day 8: 1.88 and 17: 80 mg PO once

Warfarin: 1.0 mg PO daily prior to initiating chemotherapy, 2.0 mg PO daily prior to second cycle of chemotherapy (INR target 1.2- 1.5)

Concomitant Medications: Days 1, 8 and 15: irinotecan 60 mg/m2, granisetron 3 mg, Day 1: cisplatin 60 mg/m2 every 4 weeks, dexamethasone 13.2 mg, Days 2, 3, 8 and 15: 6.6 mg

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Aprepitant and Interacting First Author Significance and Study Design, Objective, and Population Drug’s Dose + Concomitant Adverse Events (Year) Comments Medications Ohno (2014)60 Study Design: Case Reports Aprepitant: Day 1: 125 mg PO, C1: transient increase in INR (>2.6) followed by Funding: none Days 2-3: 80 mg PO (C1: initiated decrease in INR (<1.6) after addition of aprepitant Population: during cycle 2 of 4 cycles during 3 of 4 chemotherapy cycles evaluated Confounding - C1: small cell lung cancer + atrial evaluated, C2: initiated cycle 1) factorsa: fibrillation, Japanese C2: Decrease in INR to 1.1 on Day 8 of dexamethasone, - C2: endometrial carcinoma + Warfarin Dosing: chemotherapy cycle 1. Pattern recurrent with 3 patients suffering pulmonary thrombosis and deep vein - C1: 3.5-3.75 mg/day subsequent chemotherapy cycles. from malignancies thrombosis, Japanese PO (target INR 1.6-2.6) that can disturb - N: 2 - C2: 4 mg/day PO anticoagulation in - Age: C1: 60 years, C2: 47 years (target INR 1.5-2.5) warfarin users, - M:F = 1:1 changes to Concomitant Medications: concomitant - C1: Day 1: carboplatin 565 medications (C1) mg (Cycle 1, doses decreased by 20% cycles 2- DIPS Score: C1: 7, 4); Days 1-3: etoposide C2: 3 170 mg (Cycle 1, doses decreased by 20% cycles 2- 4),dexamethasone 6.6 mg; Day 2: metoclopramide, chlorpromazine, Days 4-8: metformin (cycle 1 only); Day 12: lenograstrim; granisetron (days administered and dose NR) - Chronic medications: L- carbocsteine 1500 mg/day, epalrestat 150 mg/day, carvedilol 2.5 mg/day (dose reduced on Day 8 of Cycle 1), lansoprazole 15 mg/day, nicorandil 45 mg/day, pitavastatin 1 mg/day, mecobaramin 0.45 mg/day, aspirin 100 mg/day, clopidogrel 75 mg/day, alprazolam 4.5 mg/day, estazolam 2 mg/day, acarbose 300

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Aprepitant and Interacting First Author Significance and Study Design, Objective, and Population Drug’s Dose + Concomitant Adverse Events (Year) Comments Medications mg/day, rebamipide 300 mg/day, insulin aspart 15 IU/day, granisetron, metoclopramide, chlorpromazine - C2: Day 1: cisplatin 130mg, doxorubicin 70 mg; Days 1- 5: doxorubicin 1.7 g/day; Days 1-3: dexamethasone 10 mg; Days 4-5: dexamethasone 6.6 mg; ramosetron (days administered and dose NR) - Chronic medications: magnesium oxide 1 g daily, daikenchuto 7.5 g daily Nakano Study Design: case report Aprepitant: Day 1: 125 mg PO INR increased from baseline: INR 1.89 (40 days prior Funding source: NR (2015)61 once; Days 2 and 3: 80 mg PO to chemotherapy) to 3.05 on day 2 of chemotherapy Population: squamous cell carcinoma including once daily and 4.17 on day 5. Confounding urothelial carcinoma + deep vein thrombosis INR increased to 4.5 on day 6 of second factorsa: cisplatin, - N: 1 Warfarin: 1 mg/day PO (INR chemotherapy cycle. gemcitabine, - Age: 64 years target 2-3) dexamethasone - M:F = 1:0 Concomitant Medications: Day 1: DIPS Score: 6 cisplatin 70 mg/m2, Days 1 and 8: gemcitabine 1000 mg/m2, dexamethasone 6.6mg; Days 1-3 and Day 8: granisetron 3 mg; Chronic medications: pitavastatin calcium 1 mg/day, sennoside 24 mg/day, nitrazepam 5 mg/day Inagaki Study Design: Case Report Aprepitant: NR Unstable PT-INR resulting in left external iliac vein Funding source: NR (2015)62 thrombosis Population: clear cell carcinoma + pulmonary Warfarin: NR Confounding embolism factorsa: cisplatin, - N: 1 Concomitant Medications: irinotecan - Age: 63 years irinotecan, cisplatin - M:F = 0:1 DIPS Score: 2

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Aprepitant and Interacting First Author Significance and Study Design, Objective, and Population Drug’s Dose + Concomitant Adverse Events (Year) Comments Medications Okada (2016)63 Study Design: Case Report Aprepitant: Day 1: 125 mg PO Change in INR from baseline during IE: Funding source: NR once, Days 2 and 3: 80 mg PO Cycle 1: INR 2.61 prior to IE; INR 5.45 on Day 3; Population: rhabdomyosarcoma and occlusion once daily during vincristine, Cycle 2: INR 2.85 prior to IE; INR 4.83 on Day 2. Confounding of left middle cerebral artery, Japanese doxorubicin and Pattern recurrent on Cycles 3 and 4. factorsa: ifosfamide, - N: 1 cyclophosphamide (VDC) and etoposide, - Age: 15 years ifosfamide and etoposide (IE) Change in INR from baseline during VDC: dexamethasone - M:F = 1:0 None. Warfarin: 2 mg/day PO (Cycle 1 DIPS Score: 3 of VDC and IE) and 2.5 mg/day PO (Cycle 2 of VDC and IE)

Concomitant Medications: VDC: Days 1: vincristine 1.5 mg/m2 IV, doxorubicin 37.5 mg/m2 IV, cyclophosphamide 1200 mg/m2 IV, mesna 600 mg IV q6h Day 2: doxorubicin 37.5 mg/m2 IV IE: Days 1-5: etoposide 100 mg/m2 IV and ifosfamide 1800 mg/m2 IV, mesna 600 mg IV q6h

With all chemotherapy: ondansetron 4 mg IV q12h, dexamethasone 3.3 mg IV q12h and famotidine 20 mg IV q12h

After IE while cytopenic: fluconazole 100 mg PO daily Takaki (2016)64 Study Design: Retrospective study Aprepitant: NR Mean warfarin doses (±SD): Funding Source: - One week before aprepitant: 3.72 ± 1.25 Grant-in-Aid for Objective: to clarify effects of drug-drug Warfarin: patient specific mg Young Scientists interaction between aprepitant and warfarin - One week after aprepitant: 3.37 ± 0.89 mg from the Ministry of for long-term monitoring on PT-INR in patients Concomitant medications: - Two weeks after aprepitant: 3.90 ± 1.24 Education, Culture, receiving anticancer therapy patient-specific including: mg Sports, Science and omeprazole, gliclazide, - Three weeks after aprepitant: 3.90 ± 1.39 Technology of Japan Population: allopurinol, prednisolone, mg

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Aprepitant and Interacting First Author Significance and Study Design, Objective, and Population Drug’s Dose + Concomitant Adverse Events (Year) Comments Medications - N: 14 (34 cycles with aprepitant) aspirin, acetaminophen, - p>0.05 Confounding - Mean age: 59 years (range: 33-78 levofloxacin, thiamazole, factorsa: interacting years) tramadol, erythromycin, Mean PT-INR values (±SD): concomitant - M:F = 6:8 cisplatin, dexamethasone, - One week before aprepitant: 1.68 ± 0.44 medications betamethasone, paclitaxel, - One week after aprepitant: 2.30 ± 0.67 carboplatin, naproxen, - Two weeks after aprepitant: 1.35 ± 0.33 sulfamethoxazole, etoposide, - Three weeks after aprepitant: 1.55 ± 0.52 loxoprofen, bezafibrate, - Mean values of PT-INR for 27/30 cycles trimethoprim increased the week after aprepitant administration vs week before aprepitant (p=0.0000149) - Mean values of PT-INR for 25/28 cycles decreased 2 weeks after aprepitant compared to the week before aprepitant (p=0.00069)

Mean Warfarin Sensitivity Index (WSI) [=mean PT- INR/mean daily warfarin dose]: - One week before aprepitant: 0.51 ± 0.22 - One week after aprepitant: 0.74 ± 0.30 - Two weeks after aprepitant: 0.38 ± 0.15 - Three weeks after aprepitant: 0.46 ± 0.29 - Mean values of WSI for 26/30 cycles increased the week after aprepitant administration vs week before aprepitant (p=0.000139) - Mean values of WSI for 22/28 cycles decreased 2 weeks after aprepitant compared to the week before aprepitant (p=0.00354) PO, by mouth; IV, intravenously; N, number of study subjects; M, male; F, female; NR, not reported; SD, standard deviation; INR, international normalized ration; SSRI/SNRI, selective serotonin reuptake inhibitor/serotonin-norepinephrine reuptake inhibitor aConfounding factors may include other medications that a study subject may have received that would alter the pharmacokinetic disposition of the interacting drug or anything that was mentioned in the study paper that would impact the pharmacokinetic disposition of the interacting drug

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Supplementary Table B10. Drug interaction probability scale evaluation for case reports First Author (Year) Verwimp- Shindorf Shindorf Sejourne Sejourne Sunela Sunela Yano Yano Ohno Ohno Score Mir Durand Jarkowski McDonnel Nakano Inagaki Okada Ruellen Sassier Hoeks (2013), (2013), (2014), (2014), (2016), (2016), (2011), (2011), (2014), (2014), Question (2011) (2007) (2008) l (2012) (2015) (2015) (2016) (2012) (2016) Options (2012) Case 1 Case 2 Case 1 Case 2 Case 1 Case 2 Case 1 Case 2 Case 1 Case 2 Previous Yes = + 1 credible reports No = - 1 of interaction in Unknown 1 -1 -1 1 1 1 1 1 1 0 0 1 1 1 1 1 1 1 -1 1 humans? or NA = 0 Observed interaction consistent with Yes = + 1 known No = - 1 interactive Unknown 1 0 1 0 0 0 0 0 0 0 0 1 1 1 1 1 0 1 0 1 properties of or NA = 0 precipitant drug? Observed interaction Yes = + 1 consistent with No = - 1 known Unknown 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 0 1 0 1 interactive or NA = 0 properties of object drug? Event consistent Yes = + 1 with known or No = - 1 reasonable time Unknown 1 1 1 1 1 1 1 1 0 1 1 1 1 1 1 -1 0 1 -1 1 course of or NA = 0 interaction? Interaction remit upon Yes = + 1 dechallenge of No = - 2 precipitant drug Unknown 0 1 0 0 0 0 0 0 0 0 -2 0 0 0 -2 1 0 0 0 0 with no change or NA = 0 in object drug? Interaction reappeared Yes = + 2 when No = - 1 precipitant drug Unknown 2 2 2 0 0 0 0 0 0 0 0 2 2 2 0 2 0 -1 0 0 re- or NA = 0 administered? Reasonable Yes = - 1 alternative No = + 1 causes for the Unknown 0 0 0 0 -1 -1 -1 -1 -1 -1 -1 0 0 0 0 0 0 0 0 -1 event? or NA = 0 Object drug detected in blood or other Yes = + 1 fluids in No = 0 concentrations Unknown 1 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 consistent with or NA = 0 the proposed interaction? Drug interaction confirmed by any objective Yes = + 1 evidence No = 0 consistent with Unknown 0 1 1 1 1 1 1 0 1 1 1 1 1 1 1 1 1 0 0 0 the effects on or NA = 0 the object drug (other than drug

238

First Author (Year) Verwimp- Shindorf Shindorf Sejourne Sejourne Sunela Sunela Yano Yano Ohno Ohno Score Mir Durand Jarkowski McDonnel Nakano Inagaki Okada Ruellen Sassier Hoeks (2013), (2013), (2014), (2014), (2016), (2016), (2011), (2011), (2014), (2014), Question (2011) (2007) (2008) l (2012) (2015) (2015) (2016) (2012) (2016) Options (2012) Case 1 Case 2 Case 1 Case 2 Case 1 Case 2 Case 1 Case 2 Case 1 Case 2 concentrations) ? Interaction greater when precipitant drug Yes = + 1 dose was No = - 1 increased or less Unknown 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 when the or NA = 0 precipitant drug dose was decreased? TOTAL SCORE 7 6 6 4 3 3 3 2 2 2 0 7 7 7 3 6 2 3 -2 3

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D. Victim Drug Routes of Metabolism, Transporters where Victim Drugs are Substrates and Renal Elimination Victim drug CYPs where victim drug is Transporter gene where Renal Elimination a substrate and other victim drug is a substrate (% dose recovered in urine) enzymes that are involved in metabolism of victim drug Antineoplastic Agents Bosutinib65 CYP3A4 ABCB1 3% Cabazitaxel65 CYP3A4/5 (80-90%) ABCB1 3.7% (2.3% as unchanged CYP2C8 drug) Cyclophosphamide66 CYP 2B6, CYP 2C9, CYP No known information 5% to 25% as unchanged 3A4/5 (major) drug CYP 2A6, CYP 2C8, CYP 2C19 (minor)

ALDH1A1 (major), ALDH3A1, ALDH5A1 (minor) [responsible for metabolism of cyclophosphamide metabolite aldosphosphamide] Dinaciclib CYP3A467 ABCB1, ABCG2, ABCC1 No published information (in vitro)68 available Docetaxel66, 69 CYP3A4/3A5 SLCO1B3, ABCB1, ~6% of radioactive-labelled ABCC2, ABCG2, ABCC1 docetaxel Erlotinib65, 66 CYP3A4, CYP 1A1 (major) ABCB1, ABCG2 8% (0.3% of as unchanged CYP3A5, CYP1A2 (minor) drug following 100 mg dose) Ifosfamide65, 66 CYP3A4, CYP 2B6 (minor) None 70-80% radioactive CYP 3A7, CYP 2A6, CYP 5g/m2 dose; 2C8, CYP 2C9, CYP 2C19 12-18% unchanged drug (minor) following 1.6-2.4g/m2 dose ALDH1A1 and retinal dehydrogenase 1 [responsible for metabolism of ifosfamide metabolite aldoifosfamide] Melphalan Chemical hydrolysis; not ABCB1, LAT1, LAT2, 10% ± 4.5%66 actively metabolized66, 70 SLC7A771, 72 Pazopanib CYP3A4 (major) ABCB1, ABCG273 <4%65 CYP1A2, CYP2C8 (minor)65 Thiotepa CYP3A4 (major ABCC1 (glutathione 0.1-2%; TEPA: 4%; CYP2B6 (minor)74 conjugate of thiotepa)76 unidentified metabolites with alkylating activity: 13-24%74 glutathione S-transferase (GST) isoenzymes A1-1 and P1-175 Vinorelbine CYP3A4 ABCB1, ABCC2, ABCC3, 18%, 11% as unchanged drug ABCC1, ABCC10, RALBP165 Non-Antineoplastic Agents Alcohol CYP2E1 No information identified ~2% unchanged77

Peroxisomal catalase in search Aldehyde dehydrogenase65 240

Victim drug CYPs where victim drug is Transporter gene where Renal Elimination a substrate and other victim drug is a substrate (% dose recovered in urine) enzymes that are involved in metabolism of victim drug Dexamethasone CYP3A465 ABCB165 9% (60% dexamethasone sulfate)78 Digoxin Hepatic, but not dependant on ABCB1,79 ABCB480 50-70% unchanged drug65 CYP-P450 system65 SLC51A, SLC51B81 OATP4C182 Dolasetron CYP2D6 (major) No information identified ~67% (dolasetron: <1% 83 CYP3A4 (minor) in search excreted unchanged in urine; hydrodolasetron: 53% to 61% of the total dose)77 Granisetron CYP3A483 ABCB184 48% (metabolites)65 CYP1A165 Methylprednisolone CYP3A465 ABCB165 1.3% [oral], 9.2% [IV succinate] unchanged drug77 Midazolam CYP3A4 ABCB165 <0.5% unchanged; 45% to UGT1A4 57% as 1-hydroxymethyl UGT2B7 midazolam conjugate66 UGT2B466 Ondansetron CYP1A2, CYP3A4, CYP2D6 SLC22A1,85 ABCB186 ~5% unchanged drug; 44- 60% as metabolites77 Hepatic metabolism via hydroxylation, followed by glucuronide or sulfate conjugation77 Oxycodone CYP2D6, CYP3A465 No information identified Urine (~19% as parent; >64% in search as metabolites)77 Palonosetron CYP2D6 (major) Urine (80%; 40% as CYP3A4 and CYP1A2 unchanged drug)77 (minor)65 Paroxetine CYP2D6 ABCB187 64% of a 30 mg oral solution Hepatic metabolism. of paroxetine (2% unchanged 65 Glucuronide and sulfate drug; 62% as metabolites) conjugation65 Prednisolone CYP3A4 (minor) ABCB188 Excreted renally77

Sulfation, glucuronidation77 Quetiapine CYP3A4 (major) ABCB165 <1% unchanged drug; 73% CYP2D6 (minor)77 metabolites65

Oxidation, hydroxylation65 Tacrolimus CYP3A477 ABCB1,77 ABCA565 <1% as unchanged drug77 Tolbutamide65, 77 CYP2C9 (major), CYP2C19 No information identified 75% to 85% primarily as (minor) in search metabolites Warfarin S-Warfarin: CYP2C9 ABCB166 92%, primarily as R-Warfarin: CYP2C19, metabolites77 CYP1A2, CYP1A1, CYP3A4, CYP2C8, CYP2C1866

241

E. References

1. Downs SH, Black N. The feasibility of creating a checklist for the assessment of the methodological quality both of randomised and non-randomised studies of health care interventions. J Epidemiol Community Health. 1998;52(6):377-84.

2. Hsyu PH, Matschke K, Soriano-Pignataro D. An open-label, randomized, 2-period crossover study to evaluate the effect of a single oral dose of aprepitant, a moderate CYP3A inhibitor on bosutinib administered orally to healthy subjects. 2015 AAPS Annual Meeting and Exposition; October 25-29, 2015; Orlando, USA.

3. Sarantopoulos J, Mita AC, Wade JL, Morris JC, Rixe O, Mita MM, et al. Phase i study of cabazitaxel plus cisplatin in patients with advanced solid tumors: Study to evaluate the impact of cytochrome P450 3A inhibitors (aprepitant, ketoconazole) or inducers (rifampin) on the pharmacokinetics of cabazitaxel. Cancer Chemoth Pharm. 2014;74(6):1113-24.

4. Walko CM, Combest AJ, Spasojevic I, Yu AY, Bhushan S, Hull JH, et al. The effect of aprepitant and race on the pharmacokinetics of cyclophosphamide in breast cancer patients. Cancer Chemotherapy & Pharmacology. 2012;69(5):1189-96.

5. Bubalo JS, Cherala G, McCune JS, Munar MY, Tse S, Maziarz R. Aprepitant pharmacokinetics and assessing the impact of aprepitant on cyclophosphamide metabolism in cancer patients undergoing hematopoietic stem cell transplantation. Journal of Clinical Pharmacology. 2012;52(4):586-94.

6. de Jonge ME, Huitema AD, Holtkamp MJ, van Dam SM, Beijnen JH, Rodenhuis S. Aprepitant inhibits cyclophosphamide bioactivation and thiotepa metabolism. Cancer Chemotherapy & Pharmacology. 2005;56(4):370-8.

7. Zhang D, Mita M, Shapiro GI, Poon J, Small K, Tzontcheva A, et al. Effect of aprepitant on the pharmacokinetics of the cyclin-dependent kinase inhibitor dinaciclib in patients with advanced malignancies. Cancer Chemother Pharmacol. 2012;70(6):891-8.

8. Kaneta T, Fujita K, Akiyama Y, Kawara K, Sunakawa Y, Kawachi A, et al. No pharmacokinetic alteration of docetaxel following coadministration of aprepitant 3 h before docetaxel infusion. Cancer Chemotherapy & Pharmacology. 2014;74(3):539-47.

9. Nygren P, Hande K, Petty KJ, Fedgchin M, van Dyck K, Majumdar A, et al. Lack of effect of aprepitant on the pharmacokinetics of docetaxel in cancer patients. Cancer Chemother Pharmacol. 2005;55(6):609-16.

10. Mir O, Blanchet B, Goldwasser F. More on aprepitant for erlotinib-induced pruritus. New Engl J Med. 2011;364(5):487.

11. Durand JP, Gourmel B, Mir O, Goldwasser F. Antiemetic neurokinin-1 antagonist aprepitant and ifosfamide-induced encephalopathy. Ann Oncol. 2007;18(4):808-9.

242

12. Vadhan-Raj S, Zhou X, Spasojevic I, Ravi V, Araujo D, Somaiah N, et al. Randomised, cross over study of fosaprepitant (single dose vs two doses) for nausea and vomiting in Sarcoma patients receiving multi-day chemotherapy. Support Care Cancer. 2015;1):S131-S2.

13. Imbs DC, Dieras V, Bachelot T, Campone M, Isambert N, Joly F, et al. Pharmacokinetic interaction between pazopanib and cisplatin regimen. Cancer Chemotherapy & Pharmacology. 2016;77(2):385-92.

14. Loos WJ, de Wit R, Freedman SJ, Van Dyck K, Gambale JJ, Li S, et al. Aprepitant when added to a standard antiemetic regimen consisting of ondansetron and dexamethasone does not affect vinorelbine pharmacokinetics in cancer patients. Cancer Chemother Pharmacol. 2007;59(3):407-12.

15. Egerer G, Eisenlohr K, Gronkowski M, Burhenne J, Riedel KD, Mikus G. The NK1 receptor antagonist aprepitant does not alter the pharmacokinetics of high-dose melphalan chemotherapy in patients with multiple myeloma. Br J Clin Pharmacol. 2010;70(6):903-7.

16. McCrea JB, Majumdar AK, Goldberg MR, Iwamoto M, Gargano C, Panebianco DL, et al. Effects of the neurokinin1 receptor antagonist aprepitant on the pharmacokinetics of dexamethasone and methylprednisolone. Clin Pharmacol Ther. 2003;74(1):17-24.

17. Marbury TC, Ngo PL, Shadle CR, Jin B, Panebianco D, Caro L, et al. Pharmacokinetics of oral dexamethasone and midazolam when administered with single-dose intravenous 150 mg fosaprepitant in healthy adult subjects. Journal of Clinical Pharmacology. 2011;51(12):1712-20.

18. Nakade S, Ohno T, Kitagawa J, Hashimoto Y, Katayama M, Awata H, et al. Population pharmacokinetics of aprepitant and dexamethasone in the prevention of chemotherapy-induced nausea and vomiting. Cancer Chemother Pharmacol. 2008;63(1):75-83.

19. Takahashi T, Nakamura Y, Tsuya A, Murakami H, Endo M, Yamamoto N. Pharmacokinetics of aprepitant and dexamethasone after administration of chemotherapeutic agents and effects of plasma substance P concentration on chemotherapy-induced nausea and vomiting in Japanese cancer patients. Cancer Chemother Pharmacol. 2011;68(3):653-9.

20. Li SX, Pequignot E, Panebianco D, Lupinacci P, Majumdar A, Rosen L, et al. Lack of effect of aprepitant on hydrodolasetron pharmacokinetics in CYP2D6 extensive and poor metabolizers. Journal of Clinical Pharmacology. 2006;46(7):792-801.

21. Blum RA, Majumdar A, McCrea J, Busillo J, Orlowski LH, Panebianco D, et al. Effects of aprepitant on the pharmacokinetics of ondansetron and granisetron in healthy subjects. Clinical Therapeutics. 2003;25(5):1407-19.

22. Majumdar A, McCrea J, Busillo J, Panebianco D, Dru J, Constanzer M, et al. Evaluation of the effect of aprepitant on CYP3A4 activity using midazolam as a probe. Clinical Pharmacology & Therapeutics. 2003;73(2):P6-P.

23. Shadle CR, Lee Y, Majumdar AK, Petty KJ, Gargano C, Bradstreet TE, et al. Evaluation of Potential Inductive Effects of Aprepitant on Cytochrome P450 3A4 and 2C9 Activity. Journal of Clinical Pharmacology. 2004;44(3):215-23. 243

24. Majumdar AK, Yan KX, Selverian DV, Barlas S, Constanzer M, Dru J, et al. Effect of aprepitant on the pharmacokinetics of intravenous midazolam. Journal of Clinical Pharmacology. 2007;47(6):744-50.

25. Stoch SA, Gargano C, Valentine J, Braun MP, Murphy MG, Fedgchin M, et al. Double- blind crossover study to assess potential differences in cytochrome P450 3A4 activity in healthy subjects receiving ondansetron plus dexamethasone, with and without aprepitant. Cancer Chemother Pharmacol. 2011;67(6):1313-21.

26. Fujiwara Y, Toyoda M, Chayahara N, Kiyota N, Shimada T, Imamura Y, et al. Effects of aprepitant on the pharmacokinetics of controlled-release oral oxycodone in cancer patients. PLoS ONE. 2014;9(8):e104215.

27. Shah AK, Hunt TL, Gallagher SC, Cullen Jr MT. Pharmacokinetics of palonosetron in combination with aprepitant in healthy volunteers. Current Medical Research and Opinion. 2005;21(4):595-601.

28. Maie K, Okoshi Y, Takaiwa N, Kurita N, Hasegawa Y, Homma M, et al. Aprepitant does not alter prednisolone pharmacokinetics in patients treated with R-CHOP. Ann Oncol. 2014;25(1):298-9.

29. Ibrahim RB, Abidi MH, Ayash LJ, Cronin SM, Cadotte C, Mulawa J, et al. Effect of aprepitant on intravenous tacrolimus disposition in reduced intensity hematopoietic stem cell transplantation.[Erratum appears in J Oncol Pharm Pract. 2008 Dec;14(4):233]. J Oncol Pharm Pract. 2008;14(3):113-21.

30. Ngo PL, Shadle CR, Murphy MG, Jin B, Panebianco DL, Evans JK, et al. Effect of aprepitant 40 mg on cytochrome P-450 2C9 activity: A randomized, double-blind, placebo- controlled, parallel-group study in healthy young adults. Journal of Applied Research. 2009;9(4):123-31.

31. Depre M, Van Hecken A, Oeyen M, De Lepeleire I, Laethem T, Rothenberg P, et al. Effect of aprepitant on the pharmacokinetics and pharmacodynamics of warfarin. European Journal of Clinical Pharmacology. 2005;61(5-6):341-6.

32. Feuring M, Lee Y, Orlowski LH, Michiels N, De Smet M, Majumdar AK, et al. Lack of effect of aprepitant on digoxin pharmacokinetics in healthy subjects. Journal of Clinical Pharmacology. 2003;43(8):912-7.

33. Ball WA, Snavely DB, Hargreaves RJ, Szegedi A, Lines C, Reines SA. Addition of an NK1 receptor antagonist to an SSRI did not enhance the antidepressant effects of SSRI monotherapy: results from a randomized clinical trial in patients with major depressive disorder. Human Psychopharmacology. 2014;29(6):568-77.

34. Te Beek ET, Tatosian D, Majumdar A, Selverian D, Klaassen ES, Petty KJ, et al. Placebo- and amitriptyline-controlled evaluation of central nervous system effects of the NK1 receptor antagonist aprepitant and intravenous alcohol infusion at pseudo-steady state. Journal of Clinical Pharmacology. 2013;53(8):846-56.

244

35. Kameda K, Kiba T, Ogawa Y, Kimoto S, Kajiume S, Okada Y, et al. [Effect of dexamethasone on vascular pain caused by the administration of fosaprepitant dimeglumine and epirubicin hydrochloride in patients with primary breast cancer]. Gan to kagaku ryoho Cancer & chemotherapy. 2014;41(10):1255-7.

36. Sato Y, Kondo M, Inagaki A, Komatsu H, Okada C, Naruse K, et al. Highly frequent and enhanced injection site reaction induced by peripheral venous injection of fosaprepitant in anthracycline-treated patients. J. 2014;5(5):390-7.

37. Lundberg JD, Crawford BS, Phillips G, Berger MJ, Wesolowski R. Incidence of infusion-site reactions associated with peripheral intravenous administration of fosaprepitant. Support Care Cancer. 2014;22(6):1461-6.

38. Mogi A, Takamatsu Y, Fukuda M, Oda M, Kuboda T, Nishida M, et al. Evaluation of phlebitis attribute to chemotherapy in colorectal cancer patients of our institution. Ann Oncol. 2014;25:v67.

39. Fujii T, Nishimura N, Urayama KY, Kanai H, Ishimaru H, Kawano J, et al. Differential impact of fosaprepitant on infusion site adverse events between cisplatin- and anthracycline- based chemotherapy regimens. Anticancer Research. 2015;35(1):379-84.

40. Hegerova LT, Leal AD, Grendahl DC, Seisler DK, Sorgatz KM, Anderson KJ, et al. An analysis of fosaprepitant-induced venous toxicity in patients receiving highly emetogenic chemotherapy. Support Care Cancer. 2015;23(1):55-9.

41. Tsuda T, Kyomori C, Mizukami T, Taniyama T, Izawa N, Horie Y, et al. Infusion site adverse events in breast cancer patients receiving highly emetic chemotherapy with prophylactic anti-emetic treatment with aprepitant and fosaprepitant: A retrospective comparison. Molecular and Clinical Oncology. 2016;4(4):603-6.

42. Ruellan AL, Dreno B, Saint-Jean M, Joyau C, Mahe J, Veyrac G, et al. Interaction between Bexarotene and Aprepitant: The First Case of Death. Drug Saf. 2012;35(10):897-.

43. Sassier M, Peyro-Saint-Paul L, Clarisse B, Leconte A, Coquerel A, Alexandre J, et al. Chemotherapy (platinum and pemetrexed) in combination with erlotinib in non-small cell lung cancer induces major gastrointestinal toxicity: two case reports from the FLARE/GFPC 03-2013 study. Journal of Clinical Pharmacy and Therapeutics. 2016;41(4):447-8.

44. Howell JE, Szabatura AH, Hatfield Seung A, Nesbit SA. Characterization of the occurrence of ifosfamide-induced neurotoxicity with concomitant aprepitant. J Oncol Pharm Pract. 2008;14(3):157-62.

45. Ho H, Yuen C. Letter to the editor. J Oncol Pharm Pract. 2010;16(2):137-8.

46. Stern N, Lervat C, Sophie Defachelles A, Ryckewaert T, Marliot G, Sakji I, et al. Risk factors for ifosfamide-related encephalopathy (IRE) in sarcoma (S) patients (pts). Journal of Clinical Oncology Conference. 2015;33(15 SUPPL. 1).

245

47. Chenaf C, Barthelemi L, Descoeur J, Fournier-Choma C, Hillaire-Buys D, Zenut M. Ifosfamide-induced neurotoxicity, brand-name versus generic formulation: A review of the French Pharmacovigilance Database. Fundamental and Clinical Pharmacology. 2015;29:40.

48. Gupta R, Hartwell R, Khanal R, Chen J, Hayes GL, Perez A, et al. Fosaprepitant as a risk factor for ifosfamide induced encephalopathy: A single institution experience. Journal of Clinical Oncology Conference. 2016;34(no pagination).

49. Mahe J, Corradini N, Chauvin C, Joyau C, Ruellan AL, Veyrac G, et al. Retrospective study on determinants of ifosfamide induced neurotoxicity. Drug Saf. 2015;38 (10):1001.

50. Jarkowski IA. Possible contribution of aprepitant to ifosfamide-induced neurotoxicity. Am J Health-Syst Pharm. 2008;65(23):2229-31.

51. McDonnell AM, Rybak I, Wadleigh M, Fisher DC. Suspected serotonin syndrome in a patient being treated with methylene blue for ifosfamide encephalopathy. J Oncol Pharm Pract. 2012;18(4):436-9.

52. Shindorf ML, Manahan KJ, Geisler JP. The interaction of ifosfamide and aprepitant in gynecologic malignancies. Gynecologic Oncology Case Reports. 2013;6:34-5.

53. Sejourne A, Noal S, Boone M, Bihan C, Sassier M, Andrejak M, et al. Two cases of fatal encephalopathy related to ifosfamide: An adverse role of aprepitant? Case Reports in Oncology. 2014;7(3):669-72.

54. Barthelemi L, Bara E, Descoeur J, Hillaire-Buys D, Mathieu O, Sirvent N. Ifosfamide- induced encephalopathy: Symptoms and efficacy of methylene blue (MB) in the treatment and prevention of this adverse effect. Fundamental and Clinical Pharmacology. 2015;29:24.

55. Sunela K, Barlund M. Treatment and prevention of iphosphamide-induced encephalopathy. [Finnish]. Duodecim; laaketieteellinen aikakauskirja. 2016;132(4):314-7.

56. Walsh SL, Heilig M, Nuzzo PA, Henderson P, Lofwall MR. Effects of the NK1 antagonist, aprepitant, on response to oral and intranasal oxycodone in prescription opioid abusers. Addiction biology. 2013;18(2):332-43.

57. Jones JD, Speer T, Comer SD, Ross S, Rotrosen J, Reid MS. Opioid-like effects of the neurokinin 1 antagonist aprepitant in patients maintained on and briefly withdrawn from methadone. Am J Drug Alcohol Abuse. 2013;39(2):86-91.

58. Mir O, Durand JP, Boudou-Rouquette P, Giroux J, Coriat R, Cessot A, et al. Interaction between serotonin reuptake inhibitors, 5-HT3 antagonists, and NK1 antagonists in cancer patients receiving highly emetogenic chemotherapy: A case-control study. Support Care Cancer. 2012;20(9):2235-9.

59. Yano R, Kurokawa T, Tsuyoshi H, Shinagawa A, Sawamura Y, Matsunaga A, et al. Transient elevation of international normalized ratio during cisplatin-based chemotherapy in patients who are taking warfarin. Annals of Pharmacotherapy. 2011;45(10):e55.

246

60. Ohno Y, Yamada M, Yamaguchi R, Hisaka A, Suzuki H. Persistent drug interaction between aprepitant and warfarin in patients receiving anticancer chemotherapy. International Journal of Clinical Pharmacy. 2014;36(6):1134-7.

61. Nakano K, Ushijima K, Ando H, Fujimura A, Morita T. Enhancement of anticoagulant effect of warfarin in a bladder cancer patient during treatment with gemcitabine and cisplatin. International Cancer Conference Journal. 2015;4(4):254-7.

62. Inagaki Y, Suzuki T, Saeki S, Tsushita N, Sakai T, Kato T, et al. Construction of the system of treatment for deep venous thrombosis with malignant tumor in Anjo Kosei Hospital. Ann Oncol. 2015;26:vii139-vii40.

63. Okada N, Watanabe H, Kagami S, Ishizawa K. Ifosfamide and etoposide chemotherapy may interact with warfarin, enhancing the warfarininduced anticoagulant response. International Journal of Clinical Pharmacology & Therapeutics. 2016;54(1):58-61.

64. Takaki J, Ohno Y, Yamada M, Yamaguchi Y, Hisaka A, Suzuki H. Assessment of Drug- Drug Interaction between Warfarin and Aprepitant and Its Effects on PT-INR of Patients Receiving Anticancer Chemotherapy. Biological and Pharmaceutical Bulletin. 2016;39(5):863-8.

65. . Wishart DS, Knox C, Guo AC, Shrivastava S, Hassanali M, Stothard P, Chang Z, Woolsey J. Drugbank: a comprehensive resource for in silico drug discovery and exploration. Nucleic Acids Res. 2006 Jan 1;34 (Database issue):D668-72. .

66. Whirl-Carrillo M, McDonagh EM, Hebert JM, Gong L, Sangkuhl K, Thorn CF, et al. Pharmacogenomics knowledge for personalized medicine. Clin Pharmacol Ther. 2012;92(4):414-7.

67. Zhang D, Mita M, Shapiro GI, Poon J, Small K, Tzontcheva A, et al. Effect of aprepitant on the pharmacokinetics of the cyclin-dependent kinase inhibitor dinaciclib in patients with advanced malignancies. Cancer Chemoth Pharm. 2012;70(6):891-8.

68. Cihalova D, Ceckova M, Kucera R, Klimes J, Staud F. Dinaciclib, a cyclin-dependent kinase inhibitor, is a substrate of human ABCB1 and ABCG2 and an inhibitor of human ABCC1 in vitro. Biochemical pharmacology. 2015;98(3):465-72.

69. Pastina I, Giovannetti E, Chioni A, Sissung TM, Crea F, Orlandini C, et al. Cytochrome 450 1B1 (CYP1B1) polymorphisms associated with response to docetaxel in Castration- Resistant Prostate Cancer (CRPC) patients. BMC Cancer. 2010;10:511.

70. Egerer G, Eisenlohr K, Gronkowski M, Burhenne J, Riedel KD, Mikus G. The NK receptor antagonist aprepitant does not alter the pharmacokinetics of high-dose melphalan chemotherapy in patients with multiple myeloma. Br J Clin Pharmacol. 2010;70(6):903-7.

71. Hassen W, Kassambara A, Reme T, Sahota S, Seckinger A, Vincent L, et al. Drug metabolism and clearance system in tumor cells of patients with multiple myeloma. Oncotarget. 2015;6(8):6431-47.

247

72. Kuhne A, Tzvetkov MV, Hagos Y, Lage H, Burckhardt G, Brockmoller J. Influx and efflux transport as determinants of melphalan cytotoxicity: Resistance to melphalan in MDR1 overexpressing tumor cell lines. Biochemical pharmacology. 2009;78(1):45-53.

73. Deng Y, Sychterz C, Suttle AB, Dar MM, Bershas D, Negash K, et al. Bioavailability, metabolism and disposition of oral pazopanib in patients with advanced cancer. Xenobiotica. 2013;43(5):443-53.

74. Ballatori E, Roila F, Ruggeri B, Porrozzi S, Iannopollo M, Soru G, et al. The cost of chemotherapy-induced nausea and vomiting in Italy. Support Care Cancer. 2007;15(1):31-8.

75. Ekhart C, Doodeman VD, Rodenhuis S, Smits PH, Beijnen JH, Huitema AD. Polymorphisms of drug-metabolizing enzymes (GST, CYP2B6 and CYP3A) affect the pharmacokinetics of thiotepa and tepa. Br J Clin Pharmacol. 2009;67(1):50-60.

76. Deeley RG, Cole SP. Substrate recognition and transport by multidrug resistance protein 1 (ABCC1). FEBS Lett. 2006;580(4):1103-11.

77. Lexicomp Online® L-DIH, Ohio: Lexi-Comp, Inc.; [cited 2016 Sep 11]. .

78. Miyabo S, Nakamura T, Kuwazima S, Kishida S. A comparison of the bioavailability and potency of dexamethasone phosphate and sulphate in man. Eur J Clin Pharmacol. 1981;20(4):277-82.

79. Taub ME, Mease K, Sane RS, Watson CA, Chen L, Ellens H, et al. Digoxin is not a substrate for organic anion-transporting polypeptide transporters OATP1A2, OATP1B1, OATP1B3, and OATP2B1 but is a substrate for a sodium-dependent transporter expressed in HEK293 cells. Drug Metab Dispos. 2011;39(11):2093-102.

80. Morita SY, Terada T. Molecular mechanisms for biliary phospholipid and drug efflux mediated by ABCB4 and bile salts. Biomed Res Int. 2014;2014:954781.

81. Ballatori N, Christian WV, Wheeler SG, Hammond CL. The heteromeric organic solute transporter, OSTalpha-OSTbeta/SLC51: a transporter for steroid-derived molecules. Mol Aspects Med. 2013;34(2-3):683-92.

82. Smith AJ, van Helvoort A, van Meer G, Szabo K, Welker E, Szakacs G, et al. MDR3 P- glycoprotein, a phosphatidylcholine translocase, transports several cytotoxic drugs and directly interacts with drugs as judged by interference with nucleotide trapping. J Biol Chem. 2000;275(31):23530-9.

83. Ho KY, Gan TJ. Pharmacology, pharmacogenetics, and clinical efficacy of 5- hydroxytryptamine type 3 receptor antagonists for postoperative nausea and vomiting. Curr Opin Anaesthesiol. 2006;19(6):606-11.

84. Tsuji D, Yokoi M, Suzuki K, Daimon T, Nakao M, Ayuhara H, et al. Influence of ABCB1 and ABCG2 polymorphisms on the antiemetic efficacy in patients with cancer receiving cisplatin-based chemotherapy: a TRIPLE pharmacogenomics study. Pharmacogenomics J. 2016.

248

85. Tzvetkov MV, Saadatmand AR, Bokelmann K, Meineke I, Kaiser R, Brockmoller J. Effects of OCT1 polymorphisms on the cellular uptake, plasma concentrations and efficacy of the 5-HT(3) antagonists tropisetron and ondansetron. Pharmacogenomics J. 2012;12(1):22-9.

86. Scott JA, Wood M, Flood P. The pronociceptive effect of ondansetron in the setting of P- glycoprotein inhibition. Anesth Analg. 2006;103(3):742-6.

87. Sarginson JE, Lazzeroni LC, Ryan HS, Ershoff BD, Schatzberg AF, Murphy GM, Jr. ABCB1 (MDR1) polymorphisms and antidepressant response in geriatric depression. Pharmacogenetics and genomics. 2010;20(8):467-75.

88. Miura M, Satoh S, Inoue K, Kagaya H, Saito M, Inoue T, et al. Influence of CYP3A5, ABCB1 and NR1I2 polymorphisms on prednisolone pharmacokinetics in renal transplant recipients. Steroids. 2008;73(11):1052-9.

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Appendix C. Supplementary Material for Chapter 4: Relative Bioavailability of an Extemporaneous Oral Suspension of Aprepitant in Healthy Adult Volunteers

A. Aprepitant Oral Suspension Compounding Formulation

The instructions for preparation of aprepitant 20 mg/mL oral suspension, as previously published,1 are as follows:

1. Empty contents of four aprepitant 125-mg capsules (Emend®) into a mortar 2. Grind capsule contents to a fine powder using a pestle; this process will take 10 to 15 min. Do not allow capsule contents to soak in Orablend® before grinding 3. Add a small amount of Orablend® to the fine powder and triturate to a smooth paste; ensure that there are no lumps 4. Add more Orablend® to make a liquid; transfer to a graduate 5. Rinse out mortar with Orablend® and add to graduate 6. Then, qs to final volume of 25 mL with Orablend® 7. Packaged in PET or glass bottles, label and assign expiry (no longer than 90 days), and refrigerate B. Extemporaneous Aprepitant Oral Suspension Data vs Historical Aprepitant Capsule Data

Supplementary Table C1. Comparison of the extemporaneous oral aprepitant suspension data to the historical aprepitant data in children and adults PK 0.5 to 2 to 6 to Study Data – >18 years4,5 Parameter <2 years2,3 <6 years2,3 <12 year2,3 Oral Suspension Aprepitant 3 mg/kg 3 mg/kg 3 mg/kg 125 mg 125 mg Dose Oral Oral Oral Extemporaneous Formulation Capsule suspensiona suspensiona suspensiona Oral suspension 1539b (95% Mean C 1530b (95% CI: max 1810 ± 925 1840 ± 933 1800 ± 1610 CI: 1339 to (ng/mL) 1290 to 1815) 1769) Mean T max 7.3 ± 8.28 4.9 ± 2.20 6.4 ± 7.84 4c 3.98c ± 2.31 (hours) Mean 19,455b (95% 21,100 24,400 ± 19,126b (95% CI: AUC  17,300 ± 5060 CI: 17,975 to 0 24hr ± 11,800 15,800d 16,395 to 22,311) (ng∙h/mL) 21,057) Mean Half- 6.2 ± 4.12e 9.2 ± 5.57f 10.8 ± 4.27f 9 to 13 10.4 ± 5.31 life (hours) a 25 mg/mL oral suspension currently marketed in the United States and Europe bGeometric Mean cmedian dbased on data from 6 patients ebased on data from 3 patients fbased on data from 5 patients

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C. Individual Study Volunteer Data

Supplementary Table C2. Aprepitant plasma concentrations (ng/mL) for each study volunteer after administration of an aprepitant 125 mg capsule Sampling Timesa (hours) ID Sequence Perio 0 0.5 1 2 3 4 5 6 8 10-12 24 32-36 48 d APREP1 SC 2 0 0 189 693 1270 1800 969 842 628 658 301 117c 45.4 APREP2 CS 1 0 89.3 751 1190 1360 1090 634 598 613 852 206 273b 23.9 APREP3 CS 1 0 61.1 540 1180 1870 1860 911 848 949 1190 390 145 70.6b APREP4 SC 2 15.0b 32.2 261 1130 1600 1540 1110 956 1030 1150 955 1105b 625 APREP5 SC 2 0 125 925 1170 1270 1410 751 733 775 653 688 255.5c 58 APREP6 CS 1 0 30.2 313 891 1860 1560 1010 815.5c 943 1070 894 728 311.5b APREP7 CS 1 0 218 1070 1140 1310 1060 619 607 522 533 476.5b 317 193 APREP8 SC 2 0 146 978 1980 2120 2940 2020 1280 1070 965b 740 1305b 506 APREP9 CS 1 0 17.6 144 650 628 624 579 460 498 942 374 241 77 APREP10 SC 2 0 18.7 394 1250 1360 1540 1100 906 926 865 646 473 208 APREP11 SC 2 0 257 1030 2360 1880 2220 767 877 813 981 1165b 361 125 APREP12 CS 1 0 154 667 1390 1670 1500 951 928 1190 1010 829 613 332b APREP13 CS 1 0 786 3040 4160 2860 2880 1648 1594 1238 1544 902 612 502b APREP14 CS 1 0 34.5 472 1540 1776 2000 1430 1190 1720 1430 1007.5c 619 260b APREP15 SC 2 0 47.2c 762 1030 1290 1060 770 546 399 479 129 63.7 8.05 APREP16 SC 2 0 40.8c 522 2310 1810 1380 1140 760 719 791c 479 257 129 APREP17 CS 1 0 182 1250 1610 1450 1590 616 675 556c 573 789.5b 385 319

Mean, ng/mL 0.9 132 783 1510 1611 1650 1002 860 858 923 645 463 223 Median, ng/mL 0 61.1 667 1190 1600 1540 951 842 813 942 688 361 193 Standard Deviation, ng/mL 3.6 185.3 668.9 841.4 476.7 609.4 393.0 284.4 333.3 300.1 302.4 340.0 186.8 Coefficient of Variation,% 412 141 85 56 30 37 39 33 39 33 47 73 84 SC, suspension then capsule; CS, capsule then suspension aBlood sampling time may have been adjusted by up to 30 minutes during the first 5 hours post-dose and by up to 2 hours for sampling times 6 to 48 hours post-dose bSuspected outlier based on initial visual inspection. Average of 2 non-spurious samples taken. CRandomly selected sample for re-analysis where concentration on second analysis >15%. Average of 2 non-spurious samples taken.

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Supplementary Table C3. Aprepitant plasma concentrations (ng/mL) for each study volunteer after administration of aprepitant 125 mg as the extemporaneous oral suspension Sampling Timesa (hours) ID Sequence Perio 0 0.5 1 2 3 4 5 6 8 10-12 24 32-36 48 d APREP1 SC 1 0 268 643 1400 1580 1850 1110 977 1020 954 989b 222 50.4 APREP2 CS 2 0 10.3 113 439 629 846 566 624 644 843 160 66.9 9.27 APREP3 CS 2 0 68.7 207 419 908 1090 715 665 523 528 455b 99.7 13.4 APREP4 SC 1 0 69.2 230 1060 1100 1320 938 789 1040 957 658 634.5b 327 APREP5 SC 1 0 53.7 221 909 1170 1230 625 611 830 649 592 218 64.4 APREP6 CS 2 0 21.5 139 511 698 760 950b 804 902 1190 689 399 114 APREP7 CS 2 0 102 456 1220 1930 1700 914c 787 842 705 408 327 142 APREP8 SC 1 0 274 1340 1640 2500 2270 1220 955 980 1815b 566 400 140 APREP9 CS 2 0 32.8 181 880 845 743 464 456 482 773 286 186 40 APREP10 SC 1 0 233 812 1570 2220 2020 732 737 946 1100 724 339 114 APREP11 SC 1 0 205 753 1530 1305c 1360 860 829 755 1220 491 221 58.9 APREP12 CS 2 0 102 336 531 1160 1220 776 761 784 1290 736 462 136.5b APREP13 CS 2 0 232 982 1370 2120 2260 950 828 956 868 364 339b 69.6b APREP14 CS 2 0 137 468 1090 1440 1580 686 654.5c 636 674c 315.5c 229 29.1b APREP15 SC 1 0 77 461 956 1230 1600 748 643 583 516 220 104 14.8 APREP16 SC 1 0 219 591 1110 1540 1800 1030 921 667 1500 935b 398 200 APREP17 CS 2 0 539c 1240c 1960 1569c 1932 1580 920 763 937 694.5b 527 474

Mean, ng/mL 0 156 540 1094 1409 1505 874 762 786 972 546 304 118 Median, ng/mL 0 102 461 1090 1305 1580 860 787 784 937 566 327 69.6 Standard Deviation, ng/mL 0 133.2 379.0 453.6 538.4 488.4 267.7 140.7 175.2 349.5 238.8 156.6 122.3 Coefficient of Variation,% 0 86 70 42 38 33 31 19 22 36 44 52 104 SC, suspension then capsule; CS, capsule then suspension aBlood sampling time may have been adjusted by up to 30 minutes during the first 5 hours post-dose and by up to 2 hours for sampling times 6 to 48 hours post-dose bSuspected outlier based on initial visual inspection. Average of 2 non-spurious samples taken. CRandomly selected sample for re-analysis where concentration on second analysis >15%. Average of 2 non-spurious samples taken.

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Supplementary Figure C1a. Aprepitant concentration versus time plot for APREP1 4500 4000 3500 3000 2500 2000 Capsule 1500 Suspension 1000

500 Aprepitant ConcentrationAprepitant (ng/mL) 0 0 10 20 30 40 50 Time (hours)

Supplementary Figure C1b. Ln (aprepitant concentration) versus time plot for APREP1 8 7 6 5 4 Capsule 3 Suspension 2 1

Ln Ln (aprepitant(ng/mL)concentration) 0 0 10 20 30 40 50 Time (hours)

253

Supplementary Figure C2a. Aprepitant concentration versus time plot for APREP2 4500 4000 3500 3000 2500 2000 Capsule 1500 Suspension 1000

500 Aprepitant concentrationAprepitant (ng/mL) 0 0 10 20 30 40 50 Time (hours)

Supplementary Figure C2b. Ln (aprepitant concentration) versus time plot for APREP2 8 7 6 5 4 Capsule 3 Suspension 2 1

Ln Ln (aprepitant(ng/mL)concentration) 0 0 10 20 30 40 50 Time (hours)

254

Supplementary Figure C3a. Aprepitant concentration versus time plot for APREP3 4500 4000 3500 3000 2500 2000 Capsule 1500 Suspension 1000

500 Aprepitant ConcentrationAprepitant (ng/mL) 0 0 10 20 30 40 50 Time (hours)

Supplementary Figure C3b. Ln (aprepitant concentration) versus time plot for APREP3 8 7 6 5 4 Capsule 3 Suspension 2 1

Ln Ln (aprepitant(ng/mL)concentration) 0 0 10 20 30 40 50 Time (hours)

255

Supplementary Figure C4a. Aprepitant concentration versus time plot for APREP4 4500 4000 3500 3000 2500 2000 Capsule 1500 Suspension 1000

500 Aprepitant CocnentrationAprepitant (ng/mL) 0 0 10 20 30 40 50 Time (hours)

Supplementary Figure C4b. Ln (aprepitant concentration) versus time plot for APREP4 8

4 Capsule 3 Suspension 2

Ln Ln (aprepitant(ng/mL)concentration) 0 0 10 20 30 40 50 Time (hours)

256

Supplementary Figure C5a. Aprepitant concentration versus time plot for APREP5 4500 4000 3500 3000 2500 2000 Capsule 1500 Suspension 1000

500 Aprepitant concentrationAprepitant (ng/mL) 0 0 10 20 30 40 50 Time (hours)

Supplementary Figure C5b. Ln (aprepitant concentration) versus time plot for APREP5 8 7 6 5 4 Capsule 3 Suspension 2 1

Ln Ln (aprepitant(ng/mL)concentration) 0 0 10 20 30 40 50 Time (hours)

257

Supplementary Figure C6a. Aprepitant concentration versus time plot for APREP6 4500 4000 3500 3000 2500 2000 Capsule 1500 Suspension 1000

500 Aprepitant concentrationAprepitant (ng/mL) 0 0 10 20 30 40 50 Time (hours)

Supplementary Figure C6b. Ln (aprepitant concentration) versus time plot for APREP6 8 7 6 5 4 Capsule 3 Suspension 2 1

Ln Ln (aprepitant(ng/mL)concentration) 0 0 10 20 30 40 50 Time (hours)

258

Supplementary Figure C7a. Aprepitant concentration versus time plot for APREP7 2500

2000

1500

Capsule 1000 Suspension

500 Aprepitant concentrationAprepitant (ng/mL) 0 0 10 20 30 40 50 Time (hours)

Supplementary Figure C7b. Ln (aprepitant concentration) versus time plot for APREP7 8 7 6 5 4 Capsule 3 Suspension 2 1

Ln Ln (aprepitant(ng/mL)concentration) 0 0 10 20 30 40 50 Time (hours)

259

Supplementary Figure C8a. Aprepitant concentration versus time plot for APREP8 3500

3000

2500

2000

1500 Capsule Suspension 1000

500 Aprepitant concentrationAprepitant (ng/mL) 0 0 10 20 30 40 50 Time (hours)

Supplementary Figure C8b. Ln (aprepitant concentration) versus time plot for APREP8 9 8 7 6 5 4 Capsule 3 Suspension 2 1

Ln Ln (aprepitant(ng/mL)concentration) 0 0 10 20 30 40 50 Time (hours)

260

Supplementary Figure C9a. Aprepitant concentration versus time plot for APREP9 1000 900 800 700 600 500 Capsule 400 Suspension 300 200

100 Aprepitant concentrationAprepitant (ng/mL) 0 0 10 20 30 40 50 Time (hours)

Supplementary Figure C9b. Ln (aprepitant concentration) versus time plot for APREP9 8 7 6 5 4 Capsule 3 Suspension 2 1

Ln Ln (aprepitant(ng/mL)concentration) 0 0 10 20 30 40 50 Time (hours)

261

Supplementary Figure C10a. Aprepitant concentration versus time plot for APREP10 2500

2000

1500

Capsule 1000 Suspension

500 Aprepitant concentrationAprepitant (ng/mL) 0 0 10 20 30 40 50 Time (hours)

Supplementary Figure C10b. Ln (aprepitant concentration) versus time plot for APREP10 9 8 7 6 5 4 Capsule 3 Suspension 2 1

Ln Ln (aprpeitant(ng/mL)concentration) 0 0 10 20 30 40 50 Time (hours)

262

Supplementary Figure C11a. Aprepitant concentration versus time plot for APREP11 2500

2000

1500

Capsule 1000 Suspension

500 Aprepitant concentrationAprepitant (ng/mL) 0 0 10 20 30 40 50 Time (hours)

Supplementary Figure C11b. Ln (aprepitant concentration) versus time plot for APREP11 9 8 7 6 5 4 Capsule 3 Suspension 2 1

Ln Ln (aprepitant(ng/mL)concentration) 0 0 10 20 30 40 50 Time (hours)

263

Supplementary Figure C12a. Aprepitant concentration versus time plot for APREP12 1800

1600

1400

1200

1000 Capsule 800 Suspension 600

400

200

0 0 10 20 30 40 50

Supplementary Figure C12b. Ln (aprepitant concentration) versus time plot for APREP12 8 7 6 5 4 Capsule 3 Suspension 2 1

Ln Ln (aprepitant(ng/mL)concentration) 0 0 10 20 30 40 50 Time (hours)

264

Supplementary Figure C13a. Aprepitant concentration versus time plot for APREP13 4500 4000 3500 3000 2500 2000 Capsule 1500 Suspension 1000

500 Aprepitant concentrationAprepitant (ng/mL) 0 0 10 20 30 40 50 Time (hours)

Supplementary Figure C13b. Aprepitant concentration versus time plot for APREP13 9 8 7 6 5 Capsule 4 Suspension 3 2 1

Ln Ln (aprepitant(ng/mL)concentration) 0 0 10 20 30 40 50 Time (hours)

265

Supplementary Figure C14a. Aprepitant concentration versus time plot for APREP14 2500

2000

1500

Capsule 1000 Suspension

500 Aprepitant concentrationAprepitant (ng/mL) 0 0 10 20 30 40 50 Time (hours)

Supplementary Figure C14b. Ln (aprepitant concentration) versus time plot for APREP14 8 7 6 5 4 Capsule 3 Suspension 2 1

Ln Ln (aprepitant(ng/mL)concentration) 0 0 10 20 30 40 50 60 Time (hours)

266

Supplementary Figure C15a. Aprepitant concentration versus time plot for APREP15 1800 1600 1400 1200 1000 800 Capsule 600 Suspension 400

200 Aprepitant concentrationAprepitant (ng/mL) 0 0 10 20 30 40 50 Time (hours)

Supplementary Figure C15b. Ln (aprepitant concentration) versus time plot for APREP15 8 7 6 5 4 Capsule 3 Suspension 2 1

Ln Ln (aprepitant(ng/mL)concentration) 0 0 10 20 30 40 50 Time (hours)

267

Supplementary Figure C16a. Aprepitant concentration versus time plot for APREP16 2500

2000

1500

Capsule 1000 Suspension

500 Aprepitant concentrationAprepitant (ng/mL) 0 0 10 20 30 40 50 Time (hours)

Supplementary Figure C16b. Ln (aprepitant concentration) versus time plot for APREP16 9 8 7 6 5 4 Capsule 3 Suspension 2 1

Ln Ln (aprepitant(ng/mL)concentration) 0 0 10 20 30 40 50 Time (hours)

268

Supplementary Figure C17a. Aprepitant concentration versus time plot for APREP17 2500

2000

1500

Capsule 1000 Suspension

500 Aprepitant concentrationAprepitant (ng/mL) 0 0 10 20 30 40 50 Time (hours)

Supplementary Figure C17b. Ln (aprepitant concentration) versus time plot for APREP17 8 7 6 5 4 Capsule 3 Suspension 2 1

Ln Ln (aprepitant(ng/mL)concentration) 0 0 10 20 30 40 50 Time (hours)

269

D. Exploratory Analysis

A summary of the ratios for AUC0-48h (suspension/capsule) is depicted in Supplementary Figure C18. The ratio of the aprepitant oral suspension versus the oral capsule was found to be <0.5 for APREP13 and APREP14 and >1.5 for APREP1. Therefore, the geometric least squares mean and the associated 90% CI for AUC0-48h, AUC0-inf and Cmax for the study cohort were recalculated three times, each time removing one of the aforementioned study volunteers from the dataset.

Supplementary Figure C18. Ratio of the aprepitant suspension versus the capsule for area under the curve from time zero to 48 hours post aprepitant dose for all 17 study volunteersa 2

1.8

1.6

1.4

1.2

0.8 ratio (suspension/capsule) ratio

48h 0.6

- 0

AUC 0.4

0.2

Study Volunteer aThe points in red (APREP1, APREP13 and APREP14) represent the study volunteers who had a mean ratio <0.5 or >1.5

270

Supplementary Table C4. Geometric least mean squares ratio, 90% confidence intervals and variance estimates of pharmacokinetic parameters for aprepitant oral suspension versus oral capsule excluding APREP1 Geo-LS 90% Subject Pharmacokinetic Geo-LS Residual Intrasubject Intersubject Formulation mean confidence (sequence) Parameter mean varianceb variability variability ratioa interval varianceb AUC0-48h 25135 72.83- Suspension 84.3% 0.0907 0.0544 23.7% 30.8% ng∙h/mL 97.60% 29813 Capsule ng∙h/mL AUC0-inf 27234 66.37- Suspension 79.0% 0.1367 0.0767 28.2% 38.3% ng∙h/mL 93.97% 34485 Capsule ng∙h/mL Cmax 1522 74.64- Suspension 85.5% 0.06864 0.0500 22.6% 26.7% ng/mL 98.43% 1779 Capsule ng/mL Geo-LS, geometric least square; AUC0-48h, area under the concentration versus time curve from time zero to 48 hours; AUC0-inf, area under the concentration versus time curve from time zero to infinity; Cmax, maximum concentration aRatio is of the geometric least squares mean of the pharmacokinetic parameter for the aprepitant oral suspension/oral capsule*100% bVariance as obtained from the ANOVA of ln-transformed pharmacokinetic parameter

Supplementary Table C5. Geometric least mean squares ratio, 90% confidence intervals and variance estimates of pharmacokinetic parameters for aprepitant oral suspension versus oral capsule excluding APREP13 Geo-LS 90% Subject Pharmacokinetic Geo-LS Residual Intrasubject Intersubject Formulation mean confidence (sequence) Parameter mean varianceb variability variability ratioa (%) interval varianceb AUC0-48h 25121 77.38- Suspension 90.2% 0.0802 0.0604 25.0% 28.9% ng∙h/mL 105.09% 27858 Capsule ng∙h/mL AUC0-inf 27150 73.09- Suspension 86.1% 0.1283 0.0692 26.8% 37.0% ng∙h/mL 101.41% 31536 Capsule ng∙h/mL Cmax 1483 77.37- Suspension 88.2% 0.0329 0.0445 21.3% 18.3% ng/mL 100.61% 1681 Capsule ng/mL Geo-LS, geometric least square; AUC0-48h, area under the concentration versus time curve from time zero to 48 hours; AUC0-inf, area under the concentration versus time curve from time zero to infinity; Cmax, maximum concentration aRatio is of the geometric least squares mean of the pharmacokinetic parameter for the aprepitant oral suspension/oral capsule*100% bVariance as obtained from the ANOVA of ln-transformed pharmacokinetic parameter

271

Supplementary Table C6. Geometric least mean squares ratio, 90% confidence intervals and variance estimates of pharmacokinetic parameters for aprepitant oral suspension versus oral capsule excluding APREP14 Geo-LS 90% Subject Pharmacokinetic Geo-LS Residual Intrasubject Intersubject Formulation mean confidence (sequence) Parameter mean varianceb variability variability ratioa (%) interval varianceb AUC0-48h 25607 78.54- Suspension 90.9% 0.0917 0.0552 23.8% 31.0% ng∙h/mL 105.25% 28165 Capsule ng∙h/mL AUC0-inf 27698 71.79- Suspension 85.3% 0.1412 0.0768 28.3% 38.9% ng∙h/mL 101.38% 32467 Capsule ng∙h/mL Cmax 1516 74.94- Suspension 86.2% 0.0668 0.0504 22.7% 26.3% ng/mL 99.11% 1760 Capsule ng/mL Geo-LS, geometric least square; AUC0-48h, area under the concentration versus time curve from time zero to 48 hours; AUC0-inf, area under the concentration versus time curve from time zero to infinity; Cmax, maximum concentration aRatio is of the geometric least squares mean of the pharmacokinetic parameter for the aprepitant oral suspension/oral capsule*100% bVariance as obtained from the ANOVA of ln-transformed pharmacokinetic parameter

E. References

1. Dupuis LL, Lingertat-Walsh K, Walker SE. Stability of an extemporaneous oral liquid aprepitant formulation. Support Care Cancer. 2009;17(6):701-6.

2. ClinicalTrials.gov. A Study of MK-0869 (Aprepitant) and MK-0517 (Fosaprepitant) in Pediatric Participants Receiving Chemotherapy (MK-0869-134) [Internet]. Bethesda (MD): National Library of Medicine; 2000 January 7 [updated 2017 June 2; cited 2018 March 12]. Available from: https://clinicaltrials.gov/ct2/show/study/NCT00818259?term=aprepitant§=X9870156&v iew=results

3. U.S. Food and Drug Administration. Clinical Pharmacology Review [Internet]. Silver Spring (MD): U.S. Food and Drug Administration; 2016 January [cited 1 March 2018]. Available from: https://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/DevelopmentResource s/UCM467340.pdf

4. Majumdar AK, Howard L, Goldberg MR, Hickey L, Constanzer M, Rothenberg PL, et al. Pharmacokinetics of aprepitant after single and multiple oral doses in healthy volunteers. J Clin Pharmacol. 2006;46(3):291-300.

5. Merck & Co., Inc. Emend (aprepitant) Product Monograph [Internet]. Merck Sharp & Dohme Corp.; 2017 May [cited 2018 January 8]. Available from: http://www.merck.com/product/usa/pi_circulars/e/emend/emend_pi.pdf.

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