Prediction of oral drug bioavailability: from animal-based extrapolation towards the application of physiologically-based pharmacokinetic modelling and simulation A thesis submitted to the University of Manchester for the degree of Doctor of Philosophy in the Faculty of Medical and Human Sciences 2016 Andrés Miguel Olivares Morales Manchester Pharmacy School Table of contents Table of contents ........................................................................................................ 2 List of Figures ............................................................................................................. 7 List of Tables ............................................................................................................ 11 List of Abbreviations ............................................................................................... 13 Abstract ..................................................................................................................... 18 Declaration ................................................................................................................ 19 Copyright .................................................................................................................. 20 Acknowledgements ................................................................................................... 22 Chapter 1: General Introduction ............................................................................ 23 1.1 Introduction ...................................................................................................... 24 1.2 Oral bioavailability........................................................................................... 26 1.3. Factors influencing oral bioavailability .......................................................... 27 1.3.1 Oral drug absorption ................................................................................. 27 1.3.1.1 Intestinal permeability and absorption ............................................... 28 1.3.1.1.1 Anatomy of the human GI tract .................................................. 28 1.3.1.1.1.1 Structure of the small intestine ............................................. 29 1.3.1.1.1.2 Structure of the large intestine ............................................. 30 1.3.1.1.1.3 The unstirred water layer (UWL) ......................................... 31 1.3.1.1.2 Mechanisms for permeation of the intestinal membrane ............ 32 1.3.1.1.2.1 Transcellular passive diffusion ............................................ 33 1.3.1.1.2.2 Paracellular absorption ......................................................... 33 1.3.1.1.2.3 Transporter-mediated absorption ......................................... 34 1.3.1.1.2.3.1 Intestinal efflux transporters ......................................... 34 1.3.1.1.2.3.2 Intestinal uptake transporters ........................................ 36 1.3.1.1.3 In vitro and in vivo investigation of permeability ....................... 37 2 1.3.1.1.3.1 In vivo determination of permeability.................................. 37 1.3.1.1.3.2 in vitro and in silico methods for the determination of permeability............................................................................................ 38 1.3.1.1.4 Permeability and the fraction absorbed ....................................... 41 1.3.1.1.5 BCS and the rate limiting steps for drug absorption ................... 41 1.3.1.2 Solubility and dissolution ................................................................... 42 1.3.1.2.1 Solubility ..................................................................................... 42 1.3.1.2.2 Drug release ................................................................................ 43 1.3.1.2.2 Dissolution .................................................................................. 44 1.3.1.2.3 Physiological factors that alter drug dissolution and solubility .. 45 1.3.2 Hepatic and intestinal first pass metabolism ............................................. 46 1.3.2.1 Hepatic first-pass metabolism and biliary excretions ........................ 46 1.3.2.2 Intestinal first-pass metabolism.......................................................... 48 1.4 Prediction of human oral bioavailability .......................................................... 49 1.4.1 Direct extrapolation from animal models ................................................. 49 1.4.2 Physiologically-based pharmacokinetic modelling and simulation .......... 54 1.4.2.1 PBPK models in drug development ................................................... 55 1.4.2.2 PBPK models for absorption and bioavailability ............................... 56 1.5 Project aims and objectives .............................................................................. 60 1.6 List of manuscripts and author contribution statement .................................... 62 1.8 References ........................................................................................................ 65 Chapter 2: Animal versus human oral bioavailability: do they correlate? ....... 82 Chapter 3: The Use of ROC Analysis for the Qualitative Prediction of Human Oral Bioavailability from Animal Data ................................................................. 83 Chapter 4: Analysis of the impact of controlled release formulation on oral drug absorption, gut wall metabolism and relative bioavailability of CYP3A substrates using a physiologically-based pharmacokinetic model....................... 84 3 Chapter 5: Translating Human Effective Jejunal Intestinal Permeability to Surface-Dependent Intrinsic Permeability: a Pragmatic Method for a More Mechanistic Prediction of Regional Oral Drug Absorption ................................. 85 Chapter 6: Development of a novel simplified PBPK absorption model to explain the higher relative bioavailability of the OROS formulation of oxybutynin ................................................................................................................ 86 6.1 Abstract ............................................................................................................ 87 6.2 Introduction ...................................................................................................... 88 6.3 Materials and Methods ..................................................................................... 90 6.3.1 PBPK model development ........................................................................ 90 6.3.1.1 Development of OXY’s disposition model ........................................ 91 6.3.1.1.1 Disposition model parameters and parameter estimation ........... 93 6.3.1.2 Expansion of the mSAT model for mechanistic bioavailability predictions ...................................................................................................... 96 6.3.1.2.1 Drug Transit ................................................................................ 98 6.3.1.2.2 Dissolution and solubility ........................................................... 99 6.3.1.2.3 Intestinal absorption .................................................................. 100 6.3.1.2.4 Enterocyte compartments and intestinal metabolism ................ 101 6.3.2 OXY’s oral PK simulations and relative bioavailability predictions ...... 105 6.4 Results ............................................................................................................ 108 6.4.1 OXY’s disposition parameter estimation ................................................ 108 6.4.2 Mechanistic prediction of OXY’s oral pharmacokinetics ....................... 110 6.4.3 Relative bioavailability between IR and OROS formulation .................. 111 6.5 Discussion ...................................................................................................... 116 6.6 Conclusion ..................................................................................................... 122 6.7 Acknowledgements ........................................................................................ 122 6.8 References ...................................................................................................... 123 Chapter 7: Concluding remarks and future perspectives .................................. 130 4 7.1 References ...................................................................................................... 137 Appendix A1: Supplementary Material for Chapter 2 ...................................... 138 A1.1 Supplementary Tables ................................................................................. 139 Appendix A2: Supplementary Material for Chapter 3 ...................................... 140 A2.1 Supplementary Tables ................................................................................. 141 A2.2 References ................................................................................................... 148 Appendix A3: Supplementary material for Chapter 4 ....................................... 149 A3.1 Method employed for the calculation of the relative bioavailability and its 90% confidence interval (CI). .............................................................................. 150 A3.2 Calculation method for the intrinsic clearance from in vivo clearance data 151 A3.3 Supplementary Tables ................................................................................. 153 A3.4 Supplementary Figures ...............................................................................