PHARMACOKINETIC, PHARMACODYNAMIC AND PHARMACOGENETIC FACTORS ASSOCIATED WITH BUSULFAN CLINICAL PHARMACOLOGY PARTH J. UPADHYAY A thesis submitted in fulfilment of the requirements for the degree of Doctor of Philosophy School of Pharmacy Faculty of Health and Medicine The University of Sydney December 2018 | ॐ श्री गणेशाय नमः| For Bharat Bansilal Trivedi I hereby declare that this submission is my own work and to the best of my knowledge it contains no material previously published or written by another person, nor material which to a substantial extent has been accepted for the award of any degree or diploma at The University of Sydney or any other institution, except where due acknowledgement is made in the thesis. I also declare that the intellectual content of this thesis is the product of my own work, except to the extent that assistance from others in this project’s design and conception or in style, presentation and linguistic expression is acknowledged. …………………………………………….. Parth J. Upadhyay January 2019 Table of Contents Pharmacokinetic, Pharmacodynamic and Pharmacogenetic Factors Associated with Busulfan Clinical Pharmacology ........................................................................... 1 Acknowledgements ........................................................................................................... vii Presentations Arising From This Thesis ............................................................................ xii Abstract xv Abbreviations .................................................................................................................. xvii List of Tables ................................................................................................................... xxi List of Figures ................................................................................................................ xxiii List of Equations ........................................................................................................... xxvii Chapter 1. Busulfan use in Haematopoietic Stem Cell Transplantation .......................... 1 1.1 Introduction .......................................................................................................... 2 1.2 Busulfan Therapy ................................................................................................ 2 1.3 Brief History on the Development of Busulfan-Based Transplant Regimens ........ 4 1.4 Busulfan - Current Issues .................................................................................... 7 1.4.1 Busulfan dosing - Variability in Practice ................................................................ 8 1.4.2 Pharmacokinetic Variability .................................................................................. 9 1.4.3 Pharmacokinetic Association with Outcome ....................................................... 15 1.4.4 The Therapeutic Window - Does One Size Fit All? ............................................. 18 1.4.5 Dosing ................................................................................................................ 20 1.5 Busulfan Therapeutic Drug Monitoring ............................................................... 21 1.6 Summary ........................................................................................................... 23 1.7 Study Aims ........................................................................................................ 24 Chapter 2. The Patients- A detailed analysis of the patient population recruited for analysis .............................................................................................................. 26 2.1 Introduction ........................................................................................................ 27 2.2 The Study .......................................................................................................... 27 2.2.1 Protocol .............................................................................................................. 27 2.2.2 Dosing and Sample Collection ........................................................................... 28 2.2.3 Therapeutic Drug Monitoring .............................................................................. 30 2.3 The Patients ...................................................................................................... 31 2.3.1 The Population Demographics ........................................................................... 31 2.3.2 Transplant-Related Information .......................................................................... 33 2.3.3 The Diagnoses ................................................................................................... 34 2.3.4 Conditioning Regimens ...................................................................................... 35 iii 2.3.5 Toxicity Prophylaxis ........................................................................................... 37 2.3.6 The Institutions ................................................................................................... 37 2.3.7 Targets for TDM ................................................................................................. 41 Chapter 3. Characterising Pharmacokinetic Variability in the Busulfan Study Population Using Population-Pharmacokinetic Analysis....................................................... 42 3.1 Introduction ........................................................................................................ 43 3.1.1 Rationale ............................................................................................................ 43 3.1.2 Population Pharmacokinetic Modeling................................................................ 44 3.1.3 Population Pharmacokinetic Analysis of the Busulfan Study Population ............. 44 3.2 Methods............................................................................................................. 45 3.2.1 Model Development ........................................................................................... 45 3.2.2 Covariate Analysis ............................................................................................. 47 3.2.3 Determination of AUC ........................................................................................ 48 3.2.4 Post Hoc Analysis .............................................................................................. 49 3.3 Results .............................................................................................................. 50 3.3.1 The Base Model ................................................................................................. 50 3.3.2 Stochastic Model for Random Effects................................................................. 51 3.3.3 Covariate Analysis ............................................................................................. 53 3.3.4 Step-wise Covariate Modeling ............................................................................ 56 3.3.5 Other Covariates ................................................................................................ 58 3.3.6 The Final Model ................................................................................................. 59 3.3.7 Post Hoc Analyses ............................................................................................. 63 3.4 Discussion ......................................................................................................... 71 3.4.1 The Model .......................................................................................................... 71 3.4.2 Post Hoc Analysis .............................................................................................. 75 Chapter 4. Assessing the incidence of sinusoidal Obstruction Syndrome after busulfan therapy ............................................................................................................... 78 4.1 Introduction ........................................................................................................ 79 4.1.1 Sinusoidal Obstruction Syndrome ...................................................................... 79 4.1.2 The Relationship Between Busulfan and SOS ................................................... 80 4.1.3 The Study .......................................................................................................... 82 4.2 Methods............................................................................................................. 83 4.2.1 Data Collection and Analysis .............................................................................. 83 4.2.2 Exploring the Association Between Busulfan Use and SOS Incidence ............... 83 4.3 Results .............................................................................................................. 84 4.3.1 Association Between SOS and cAUC ................................................................ 85 4.3.2 Busulfan Cmax and SOS ...................................................................................... 92 iv 4.4 Discussion ......................................................................................................... 97 4.4.1 Prophylaxis and SOS ......................................................................................... 97 4.4.2 Diagnosis and SOS ............................................................................................ 98 4.4.3 Busulfan