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DEVELOPMENT and VALIDATION of a CELLULAR PHARMACOLOGY MODEL for ZIDOVUDINE and LAMIVUDINE by JOSEPH EDWARD ROWER B.S., California Lutheran University, 2008

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DEVELOPMENT and VALIDATION of a CELLULAR PHARMACOLOGY MODEL for ZIDOVUDINE and LAMIVUDINE by JOSEPH EDWARD ROWER B.S., California Lutheran University, 2008 DEVELOPMENT AND VALIDATION OF A CELLULAR PHARMACOLOGY MODEL FOR ZIDOVUDINE AND LAMIVUDINE by JOSEPH EDWARD ROWER B.S., California Lutheran University, 2008 A thesis submitted to the Faculty of the Graduate School of the University of Colorado in partial fulfillment of the requirements for the degree of Doctor of Philosophy Pharmaceutical Sciences Program 2013 This thesis for the Doctor of Philosophy degree by Joseph Edward Rower has been approved for the Pharmaceutical Sciences Program by Christina Aquilante, Chair Peter L. Anderson, Advisor James Ruth Jose Ramon Castillo-Mancilla N. Karl Maluf Sam MaWhinney Date: 4/2/13 ii Rower, Joseph Edward (Ph.D., Pharmaceutical Sciences) Development and Validation of a Cellular Pharmacology Model for Zidovudine and Lamivudine Thesis directed by Associate Professor Peter L. Anderson ABSTRACT Nucleoside analog Reverse Transcriptase Inhibitors (NRTI) are a class of antiretro- virals used to prevent and treat HIV infection that possess a unique and complex phar- macology. Drugs in this class require three successive intracellular phosphorylation steps to the active nucleotide-TP form, which competes with endogenous nucleotides for incorporation into growing viral DNA strands, and when incorporated, halts viral propagation. Additionally, clinical doses of these drugs are associated with acute and chronic toxicities, further complicating clinical management of these drugs. It is expected that a comprehensive and unified understanding of NRTI cellular pharma- cology will provide valuable information to the scientific community, and ultimately to clinicians managing HIV and drug-associated toxicities. Data from an in vivo clinical study of HIV-seronegative and seropositive individuals was used to develop a com- plete cellular pharmacology model for two NRTI-ZDV and 3TC. This work focuses on the analytical methodologies for quantitating plasma and intracellular NRTI concen- trations, describing the pharmacology relevant to these drugs, and the mathematical models used to comprehensively evaluate these data. Significant drug PK findings include the decreased concentrations of intracellular-TP in HIV+ individuals, the ef- fect of SNPs in ABCG2 and other genes on plasma/intracellular PK and PD, and a linked mathematical model for the stimulation of intracellular-MP and subsequent conversion to -DP and -TP from plasma concentrations. Modeled intracellular -MP and -TP levels were evaluated for relationships with PD outcomes, such as viral load, mitochondrial DNA counts, and other clinical markers of drug-associated toxicities. iii The power of these results is limited, due to the short term of the clinical study (12 days) and the population size and diversity (43 subjects: 20 HIV-, 23 HIV+). How- ever, these results successfully explore the relationships between ZDV and 3TC PK, PD, and PG, and provide a foundation for further evaluation and replication of these associations in a larger and more diverse population over a longer study period, in an effort to individualize and improve the clinical care of HIV. The form and content of this abstract are approved. I recommend its publication. Approved: Peter L. Anderson iv DEDICATION This dissertation is dedicated to my parents, to whom I am forever indebted for continually pushing me to question and learn and evaluate. I am also grateful to all of those that have taught me, and instilled in me a passion for science. I am also extremely grateful to my wife Caitlin, for her love and support through this process, and the joy and blessing that she brings to my every moment. Finally, this work is dedicated to my grandpa, who will always be loved and is greatly missed. His battle with inclusion body myositis inspired my passion for clinical/translational medical research, a passion which comes to full fruition in this work. v ACKNOWLEDGEMENTS I wish to thank the NIH AIDS Research and Reference Reagent Program for the antiretroviral drugs used for assays; the study personnel and nursing who assisted with the clinical protocol; and the subjects who participated in the clinical studies. This work was supported by grants from NIH; R01 AI64029 (PLA), TL1 RR025778 (JER) and RR000051 (University of Colorado General Clinical Research Center Grant). vi TABLE OF CONTENTS CHAPTER Page 1 INTRODUCTION .............................. 1 1.1 SCOPE OF THE WORK . 1 1.2 LIMITATIONS . 3 2 REVIEW OF THE LITERATURE ................... 6 2.1 ANTIRETROVIRAL HISTORY . 6 2.2 ANTIRETROVIRAL PHARMACOLOGY . 11 2.3 PHARMACOMETRICS AND MODELING TECHNIQUES . 17 3 CLINICAL EXPERIENCE ........................ 23 4 ANALYTICAL METHODS AND VALIDATION RESULTS ... 32 4.1 PLASMA ZDV/3TC CONCENTRATIONS . 33 4.1.1 ANALYTICAL METHOD . 33 4.1.2 VALIDATION RESULTS . 40 4.1.3 METHOD DISCUSSION . 50 4.2 INTRACELLULAR NA-PHOSPHATE CONCENTRATIONS . 50 4.2.1 ANALYTICAL METHOD . 50 4.2.2 VALIDATION RESULTS . 56 4.2.3 METHOD DISCUSSION . 71 5 PK ANALYSIS OF ZDV/3TC ...................... 79 5.1 MODEL-INDEPENDENT ANALYSES . 82 5.1.1 ZDV . 84 vii 5.1.2 3TC . 88 5.2 DEMOGRAPHIC IMPACT ON PK . 92 5.2.1 MODEL DEVELOPMENT . 92 5.2.2 MODEL ANALYSIS . 93 5.2.3 DISCUSSION . 104 5.3 PG IMPACT ON PK . 108 5.3.1 METHODS . 109 5.3.2 RESULTS . 111 5.3.3 DISCUSSION . 128 6 PK-PG-PD PLASMA-CELLULAR METABOLITE MODEL ... 137 6.1 PLASMA-CELLULAR METABOLITE LINKED MODEL . 138 6.1.1 PK MODELING METHODS . 139 6.1.2 PK MODELING RESULTS . 143 6.2 PD ANALYSIS OF ZDV/3TC . 166 6.2.1 PK-PD AND PG-PD METHODS . 167 6.2.2 PK-PD AND PG-PD RESULTS . 168 6.3 DISCUSSION . 173 7 CONCLUSIONS ............................... 182 REFERENCES .................................. 207 APPENDIX A METHOD DEVELOPMENT AND VALIDATION REPORTS .. 208 A.1 PLASMA GEMFIBROZIL CONCENTRATIONS . 209 A.2 INTRACELLULAR D4T-TP CONCENTRATIONS . 218 B TABLES OF INDIVIDUAL PK RESULTS .............. 230 B.1 ZDV Plasma . 231 B.2 ZDV-MP . 234 B.3 ZDV-DP . 237 viii B.4 ZDV-TP . 240 B.5 3TC Plasma . 243 B.6 3TC-MP . 246 B.7 3TC-DP . 248 B.8 3TC-TP . 250 C FINAL ADAPT CODE ........................... 252 C.1 ZDV LINKED MODEL . 253 C.2 3TC LINKED MODEL . 261 ix LIST OF TABLES TABLE Page 4.1 ZDV/3TC Plasma Interassay Statistics . 45 4.2 ZDV/3TC Plasma Incurred Sample Reanalysis . 49 4.3 TFV Centric MS/MS SRM conditions . 55 4.4 ZDV Centric MS/MS SRM conditions . 55 4.5 IC Matrix Effects . 58 4.6 IC Calibrators Accuracy/Precision-TFV Centric . 59 4.7 IC Calibrators Accuracy/Precision-ZDV Centric . 60 4.8 IC QC Accuracy/Precision-TFV Centric . 62 4.9 IC QC Accuracy/Precision-ZDV Centric . 63 4.10 IC Alternative Matrices-TFV Centric . 64 4.11 IC Alternative Matrices-ZDV Centric . 65 4.12 IC Cell Number Experiment-TFV Centric . 67 4.13 IC Cell Number Experiment-ZDV Centric . 68 4.14 IC Stability-TFV Centric . 69 4.15 IC Stability-ZDV Centric . 69 5.1 Demographic Summary . 81 5.2 Population Mean ZDV PK Parameters . 84 5.3 Population Mean 3TC PK Parameters . 89 5.4 Final Model Covariate Results . 104 5.5 Final Model Drug Accumulation . 104 x 5.6 Evaluated SNPs . 110 5.7 ZDV Heat Map . 114 5.8 3TC Heat Map . 115 6.1 Linked Model Boundary Function Stability . 144 6.2 Plasma Base Model Parameters . 146 6.3 ZDV Plasma Model Parameter-Covariate Relationships . 147 6.4 3TC Plasma Model Parameter-Covariate Relationships . 148 6.5 Final Plasma Model Parameter Estimates . 149 6.6 Linked Base Model Parameters . 150 6.7 ZDV Linked Model Parameter-Covariate Relationships . 151 6.8 3TC Linked Model Parameter-Covariate Relationships . 152 6.9 Model Predicted Drug Concentrations . 152 6.10 Final ZDV Plasma Model Correlation Matrix . 155 6.11 Final 3TC Plasma Model Correlation Matrix . 155 6.12 Final ZDV Linked Model Correlation Matrix . 156 6.13 Final 3TC Linked Model Correlation Matrix . 156 A.1 IC QC Accuracy/Precision-d4T Centric . 227 A.2 IC Matrix Effects-d4T Centric . 228 A.3 IC Stability Experiments-d4T Centric . 228 B.1 ZDV Plasma Exposure . 231 B.2 ZDV Plasma Linear PK . 232 B.3 ZDV Plasma Accumulation Factor PK . 233 B.4 ZDV-MP Exposure . 234 B.5 Mean HIV- ZDV-MP PK Parameters . 235 B.6 Mean HIV+ ZDV-MP PK Parameters . 236 B.7 ZDV-DP Exposure . 237 B.8 Mean HIV- ZDV-DP PK Parameters . 238 xi B.9 Mean HIV+ ZDV-DP PK Parameters . 239 B.10 ZDV-TP Exposure . 240 B.11 Mean HIV- ZDV-TP PK Parameters . 241 B.12 Mean HIV+ ZDV-TP PK Parameters . 242 B.13 3TC Plasma Exposure . 243 B.14 3TC Plasma Linear PK . 244 B.15 3TC Plasma Accumulation Factor PK . 245 B.16 3TC-MP Exposure . 246 B.17 3TC-MP Exposure . 246 B.18 Mean 3TC-MP PK Parameters . 247 B.19 3TC-DP Exposure . 248 B.20 Mean 3TC-DP PK Parameters . 249 B.21 3TC-TP Exposure . 250 B.22 Mean 3TC-TP PK Parameters . 251 xii LIST OF FIGURES FIGURE Page 2.1 ZDV Structure . 7 2.2 3TC Structure . 9 2.3 FDA Approved Antiretrovirals . ..
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