Development of a population-based pharmacokinetic- pharmacodynamic model to simulate treatment efficacy in metastatic non-small-cell lung cancer patients on erlotinib By Michelle Lui A thesis submitted in conformity with the requirements for the degree of Master of Sciences Pharmaceutical Sciences University of Toronto © Copyright by Michelle Lui (2015) Development of a population-based pharmacokinetic- pharmacodynamic model to simulate treatment efficacy in metastatic non-small-cell lung cancer patients on erlotinib Michelle Lui Master of Sciences Pharmaceutical Sciences University of Toronto 2015 Abstract Erlotinib improves progression-free survival (PFS) in metastatic non-small-cell lung cancer (mNSCLC) patients, but cause toxicities leading to dose reductions. The survival impact of dose reductions is unknown. We constructed a population-based pharmacokinetic-pharmacodynamic (PK-PD) erlotinib model predicting PFS of mNSCLC patients, consisting of an erlotinib population PK component, a PD component describing the concentration-kill-constant relationship, and a tumour growth component tracking tumour size over time. This model was fit against clinical trial data to simulate population-based PFS estimates in mNSCLC patients and externally validated using other trial data. The model simulated population-based PFS estimates of placebo and erlotinib arms with 0.74-9.14% and 0.26-19.83% error, respectively. The model was externally validated with population-based PFS estimate errors of 11.3% and 16.7% in epidermal growth factor receptor (EGFR)-mutant and EGFR-wild-type mNSCLC, respectively. It predicted significant PFS decreases with dose reductions. This is the first population-based PK-PD erlotinib model that predicts PFS in mNSCLC patients. ii Acknowledgments This project would not have been possible without the help of many individuals. I would like to personally thank each and every patient for whom I have had the pleasure and privilege to provide care. Without their willingness to have me as their clinic pharmacist, I would not have developed my passion or knowledge in lung cancer management. As a tribute to them, this project is dedicated to all of my current and future lung cancer patients and their family members. The true masterminds of this model are Dr. Carlo De Angelis, my supervisor, and Scott Walker, who have taken me on as their Master’s student and assumed supervisory roles in my journey at Sunnybrook. Their patience, time, knowledge, mentorship and foresight have allowed me to grow throughout these two years as a clinical researcher. Carlo has been most inspirational as my role model in my growth as an oncology pharmacist and researcher. It is difficult to put into words the enormity of time and mentorship he has given me throughout these last two years. He has taught me the true meaning of being a lifelong learner in this ever-growing field, has fueled my passions in constantly improving patient outcomes and patient-centered care and has provided me ample opportunities to improve my research, clinical, presentation and grant-writing skills. He’s been a thoughtful and caring teacher, mentor and savior throughout the years in my budding career and has been very influential in my growth as a person. Scott’s passion for pharmacokinetic-pharmacodynamic modeling was truly contagious and it provided a key opportunity for me to merge two areas that I’ve always been passionate in – lung cancer management and mathematics. I am extremely grateful for the time that he takes out of his busy schedule to be so involved in this project. I am deeply honoured to have had the opportunity to work alongside both individuals and will cherish any future opportunities to work with either individual. I would like to give my thanks to Dr. Sunil Verma who took me into the thoracic clinic, which became my clinical home for two years and educational base where I learned about how to provide care for lung cancer patients. He allowed me to become part of his clinical team and eventually as part of the entire thoracic oncology team. I appreciated the time that he took to attend my advisory committee meetings and provide insight about the project. I would also like to thank the entire thoracic oncology team, particularly Dr. Jacques Raphael, Dr. Suneil Khanna, iii Dr. Yee Ung, Dr. Parneet Cheema, Dr. Susanna Cheng, Magdalene Winterhoff and the OCC Lung Nurses, for allowing me to be part of the clinical team and provide care for these lovely but unfortunate patients, as well as teaching me anything that I wanted to learn to refine my clinical skills as a pharmacist, care provider for their patients and team player in the interprofessional group. Last but most definitely not least, I would also like to thank the Pharmacy Department at the Odette Cancer Centre. They have allowed me to make my place as one of the oncology pharmacists in the team and provided every opportunity for me to babble on clinical pearls that were related to lung cancer management. It would be my great privilege and honour to continue working with such an esteemed group of clinicians beyond my journey as a Master’s student and Pharmacy Oncology Fellow. iv Table of Contents Abstract -------------------------------------------------------------------------------------------- ii Acknowledgements ------------------------------------------------------------------------------ iii Table of contents --------------------------------------------------------------------------------- v Glossary of Abbreviations ---------------------------------------------------------------------- viii List of tables -------------------------------------------------------------------------------------- x List of figures ------------------------------------------------------------------------------------- xii Chapter 1 – Introduction ------------------------------------------------------------------------ 1 Chapter 2 – Literature review ------------------------------------------------------------------ 5 2.1 Overview of non-small-cell lung cancer ------------------------------------------- 6 2.1.1 Epidemiology ---------------------------------------------------------------- 6 2.1.2 Risk factors and pathogenesis of non-small-cell lung cancer --------- 6 2.1.3 EGFR mutations ------------------------------------------------------------ 8 2.1.4 Role of erlotinib in standard treatment of metastatic non-small-cell 8 lung cancer 2.1.5 Efficacy outcomes of metastatic non-small-cell lung cancer --------- 11 2.1.6 Prognosis -------------------------------------------------------------------- 13 2.1.7 Current dosing strategies of antineoplastic agents ---------------------- 13 2.2 Pharmacokinetic-pharmacodynamic models -------------------------------------- 14 2.2.1 Population pharmacokinetics of erlotinib ------------------------------- 15 2.2.1.1 Pharmacokinetic models ----------------------------------------- 15 2.2.1.2 Population pharmacokinetics of erlotinib ---------------------- 16 2.2.2 Pharmacodynamics of erlotinib ------------------------------------------- 18 2.2.2.1 Mechanism of action of erlotinib ------------------------------- 18 2.2.2.2 Effect of erlotinib on tumour growth --------------------------- 19 v 2.2.2.3 Pharmacodynamic modelling of erlotinib --------------------- 19 2.2.2.4 Modeling cancer cell growth ------------------------------------ 21 2.2.3 Fitting of models ------------------------------------------------------------ 24 2.2.4 Validation of models ------------------------------------------------------- 25 2.3 Factors influencing efficacy of erlotinib ------------------------------------------- 26 2.3.1 Patient-based factors -------------------------------------------------------- 26 2.3.2 Tumour-based factors ------------------------------------------------------ 28 2.3.3 Measurement-based factors ------------------------------------------------ 29 2.3.4 Erlotinib-based factors ----------------------------------------------------- 30 2.3.4.1 Factors affecting population pharmacokinetics of erlotinib 30 2.3.4.1.1 Absorption ----------------------------------------------- 30 2.3.4.1.2 Distribution ---------------------------------------------- 31 2.3.4.1.3 Metabolism ---------------------------------------------- 32 2.3.4.2 Factors affecting pharmacodynamics of erlotinib ------------ 34 2.3.4.2.1 Methods of EGFR testing ------------------------------ 34 2.3.4.2.2 Intertumoral heterogeneity ----------------------------- 34 2.3.4.2.3 Intratumoral heterogeneity ----------------------------- 35 2.3.4.2.4 The tumour microenvironment ------------------------ 36 2.4 Current pharmacokinetic-pharmacodynamic models ---------------------------- 37 2.5 Current literature on the exposure-efficacy relationship of erlotinib ---------- 38 2.6 Summary ------------------------------------------------------------------------------- 40 Chapter 3 – Research objective and methodological steps --------------------------------- 41 3.1 Objective ------------------------------------------------------------------------------- 42 3.2 Methodological Steps ---------------------------------------------------------------- 42 Chapter 4 – Methods ----------------------------------------------------------------------------- 43 vi 4.1 Overview of model ------------------------------------------------------------------- 43 4.2 The pharmacokinetic model component ------------------------------------------- 43 4.3 The pharmacodynamics model component ---------------------------------------- 48 4.4 The tumour growth