THE UTILITY OF PHARMACOMETRICS IN DRUG DEVELOPMENT AND PHARMACOTHERAPY OF ANTIMICROBIALS A DISSERTATION SUBMITTED TO THE FACULTY OF THE UNIVERSITY OF MINNESOTA BY ALI AHMED ALHADAB IN PARTIAL FULFILLIMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY RICHARD C. BRUNDAGE, Advisor MARNIE L. PETERSON, Co-Advisor December 2017 © Copyright Ali A. Alhadab 2017 All Rights Reserved AKNOWLEDGEMENTS Many people without who this thesis would not have been possible deserve my sincere gratitude. First and foremost, my wholehearted thanks go to Almighty Allah, the most Merciful the most Compassionate, the one who provides me with all I need, guides me throughout my journey, and equips me with the capabilities to accomplish this work. I am thankful and honored to work under the supervision of Dr. Richard Brundage. Not only was he an adviser, but also he was a mentor, friend and father as the same time. Your help, support, guidance, encouragement and patience throughout the program were surely behind my success. Thank you for always being there for me and putting my personal needs and professional aspirations first. You have been my last resort to go to because I knew you would do your best to ensure things go the way I wish. A special thanks to my co-adviser. Dr. Marine Peterson, the person behind my acceptance into the Experimental and Clinical Pharmacology (ECP) graduate program. She was also the one who introduced me to and established the collaboration with Dr. David Boulware. I am really indebted to her in many ways and I cannot thank her enough. Without her, I would not have been in such a great program and I would not have met all the wonderful people at University of Minnesota. Dr. Peterson was also the first person who introduced to the field of pharmacometric and showed me how powerful PK-PD modeling & simulation is to guide antimicrobial therapies. And so, did she suggest to me working with Dr. Richard Brundidge. I would also like to thank Dr. Mark Kirstein, Dr. David Boulware, and Dr. David Vock for serving on my committee. Your dedicated time and constructive feedback are highly appreciated. i I want to extend my great appreciation to all ECP staff and faculty for this memorable and rich educational experience. In particular, I would like to express my deepest gratitude to Carol Dickinson who worked me closely when I was transitioning to Minnesota and during my first year. She made sure I was well-taken care of. I am also very thankful to University of Minnesota for awarding me the First Year Fellowship and the ECP department for granting me the Coin Foundation Fellowship in 2015 and 2016. The fellowships helped me focus more on my academic coursework and research activities. Likewise, I would like to thank the Clinical & Translational Science Institute at University of Minnesota for the 2015 Summer Advanced Research Fellowship and their approval to attend the Uppsala Pharmaceutics Summer School. I am indebted to the entire Uppsala pharmacometric group for the 2-week comprehensive PK-PD modeling and simulation course, lecture notes, code snippets, and feedback about my project. The course really brought me up to speed to analyze my data confidently. In addition, I would like to thank Kyle Barron, an ECP alumnus, who developed mrgsolve R package. I saved a lot of time using the package and it allowed to use R as one platform to quickly simulate, visualize results, and build dazzling shinyApps. Finally, my sincere and deepest gratitude goes to my wonderful family: parents, siblings, beautiful wife, and angel daughter. Your unconditional love, continuous support and sacrifice are appreciated. Thank very much for everything you all have done for me. I am really blessed to have such a great family and I ask Almighty Allah to reward you for everything you have done for me. ii DEDICATION This work is dedicated to my beloved parents and family for their endless love, support and encouragement and to all advisers, mentors, teachers and individuals who helped me through my trainings. iii ABSTRACT Infectious diseases are a growing major public health concern due to the increase of antimicrobial resistance to current therapies and the lack of new drugs in development. As an alternative to developing new anti-infective drugs, my thesis research focuses on ways to optimize current antimicrobial therapies. This thesis aims specifically to utilize pharmacometric modeling and simulation that applies pharmacokinetic (PK) and pharmacodynamics (PD) principles to provide insights into ways to maximize drug effect while minimizing side effects and preventing resistance. Mathematical and statistical methods are used to develop integrated drug, body, and microbial models that quantify relationships among dose, plasma and tissue concentrations, and microbial killing. These pharmacometric models are then used to predict the outcome of various untested scenarios to select the optimal dosing regimens for confirmatory clinical testing. A dose-finding study, named COAT, was conducted to assess the PK and microbiological efficacy of adjunctive sertraline for the treatment of cryptococcal meningitis (CM) in HIV-infected Ugandans. Plasma sertraline concentrations, fungal counts in cerebral spinal fluid, and survival outcome were modeled to characterize the dose-exposure-response-outcome relationships of sertraline as an antifungal. Sertraline PK was influenced by body weight and co-administration anti-retroviral therapy (ART) non-nucleotide reverse transcriptase inhibitors. The addition of sertraline to the standard induction therapy of Cryptococcus increased fungal clearance rate from cerebrospinal fluid 34-48% compared to COAT trial, a similar historical study in which patients received CM induction therapy without sertraline. The effect of sertraline on Cryptococcus fungal clearance was similar irrespective of the daily dose patients received iv (100 – 400 mg). The 2-week survival rates were lower for females and patients receiving sertraline 100 and 400 mg daily. Further, a model-based meta-analysis of sertraline published PK studies in healthy adults were performed to estimate oral bioavailability, absorption and plasma clearance. Sertraline had super-proportional increase in exposure with dose attributed to the nonlinear increase of bioavailability with dose. The findings were then used to build and validate a physiological-based pharmacokinetic (PBPK) model in order to assess the potential clinical use of sertraline as an antimicrobial. PBPK oral stimulations indicated that therapeutic doses (50-200 mg) of sertraline do not produce clinical concentrations required for antimicrobial effects (MIC = 1 – 12 mg/L). In addition, a population PK model of aminoglycoside antibiotic, amikacin, was developed in pediatric cancer patients and used to predict the probability of various dosing regimens to achieve PK-PD targets predictive of efficacy and toxicity. Simulation indicated ≥ 60 mg/kg administered once daily are expected to have a 97.5% probability in which the unbound fCmax/MIC ≥ 8 is achieved in 80% of pediatric patients weighing 8-70 kg and the unbound fCmin < 10 mg/L in almost all patients. Furthermore, the population PK model was linked to an adaptive PD (ARPD) model of amikacin against Pseudomonas aeruginosa built using in vitro literature time-kill curve data to perform PK-ARPD simulation. The results suggested that amikacin 90 mg/kg given in two divided doses (45 mg/kg twice a day) will hit safety (fCmin < 10 mg/L) and efficacy (fCmax/MIC ≥ 8 ) targets, and be associated with a lower rate of bacterial resistance evident by bacterial counts being below the limit of detection until day 7. v This thesis demonstrates the vital role of pharmacometric modeling and simulation in the rational selection of dose regimens of antimicrobial agents. The application of this tool in drug development process and clinical practice can guard against the costly late-stage failures and improve clinical outcomes of patient care, respectively. vi TABLE OF CONTENT LIST OF TABLES x LIST OF FIGURES xi 1 THESIS SCOPE AND OBJECTIVES 1 2 IMPACT OF PHARMACOMETRICS ON DRUG DEVELOPMENT AND PHARMACOTHERAPY OF ANIT-MICROBIALS 2 2.1 SUMMARY ...................................................................................................... 2 2.2 INTRODUCTION ............................................................................................ 2 2.2.1 Problem ............................................................................................3 2.2.2 Causes ..............................................................................................5 2.2.3 Solutions ........................................................................................10 2.3 PHARMACOMETRICS................................................................................. 15 2.3.1 Definition and Principles ...............................................................15 2.3.2 Acceptance .....................................................................................20 2.3.3 Advantages over Conventional Analyses .....................................22 2.3.4 Challenges for Implementation .....................................................24 2.3.5 Current Applications ......................................................................26 2.4 CONCLUSION ............................................................................................... 31 3 PHARMCOKINETICS-PHARMACODYNAMICS (PK-PD) OF SERTRALINE AN ANTIFUNGAL IN HIV-INFECTED PATIENTS WITH CRYPTOCOCCAL