Prediction of Human Nonlinear Pharmacokinetics of a New Bcl-2 Inhibitor Using PBPK Modeling and Interspecies Extrapolation Strategy

Abstract

S 55746 ((S)-N-(4-hydroxyphenyl)-3- (6-(3-(morpholinomethyl)-1,2,3,4tetrahydroisoquinoline-2-carbonyl)benzo [d][1,3]dioxol-5-yl)-N-phenyl-5,6,7,8-tetrahydroindolizine-1-carboxamide) is a new selective Bcl-2 (B-cell lymphoma 2) inhibitor developed by Servier Laboratories and used to restore apoptosis functions in cancer patients. The aim of this work was to develop a translational approach using physiologically based (PB) pharmacokinetic (PK) modeling for interspecies extrapolation to anticipate the nonlinear PK behavior of this new compound in patients. A PBPK mouse model was first built using a hybrid approach, defining scaling factors (determined from in vitro data) to correct in vitro clearance parameters and predicted Kp (partition coefficient) values. The qualification of the hybrid model using these empirically determined scaling factors was satisfactorily completed with rat and dog data, allowing extrapolation of the PBPK model to humans. Human PBPK simulations were then compared with clinical trial data from a phase 1 trial in which the drug was given orally and daily to cancer patients. Human PBPK predictions were within the 95% prediction interval for the eight dose levels, taking into account both the nonlinear dose and time dependencies occurring in S 55746 kinetics. Thus, the proposed PK interspecies extrapolation strategy, based on preclinical and in vitro information and physiologic assumptions, could be a useful tool for predicting human plasma concentrations at the early stage of drug development.

Phase 0/microdosing approaches: time for mainstream application in drug development?

“…Both sources of non-linearity can be incorporated into pharmacokinetic prediction of therapeutic doses through physiologically based pharmacokinetic (PBPK) modelling and simulation, which has made considerable progress in recent years (see later, Fig. 3 and Supplementary information C) [37][38][39][40] . Since the different approaches (microdosing and PBPK modelling) use non-overlapping sources of data and theoretical constructs, they are often complementary and indeed synergistic when used together (box 2).…”

“…Results of validation efforts demonstrate prediction of therapeutic-level drug disposition following microdose administration in 68% or 94% of cases depending on whether the administration is enteral or parenteral, respectively 36 . In addition, greater insight into non-linear mechanisms, their impact on extrapolation of subtherapeutic to therapeutic-level exposures and their management through modelling further increased the reliability and validity of extrapolation 29,33,[37][38][39][40] (discussed further later). In parallel, academic and commercial entities continued research into methods and applications 18, (Supplementary information A) to expand the effectiveness of these approaches, and sponsors have increasingly used phase 0 approaches in developmental scenarios not effectively addressed by traditional approaches [9][10][11][12][13][14]16,35,37,38,41, (Table 3; Supplementary information A).…”

Development and Evaluation of a Physiologically Based Pharmacokinetic Drug-Disease Model of Propranolol for Suggesting Model Informed Dosing in Liver Cirrhosis Patients

“…13,14,23,43 The average fold error (AFE) and root mean square error (RMSE) were calculated for further verification of the developed PBPK model. 14,44 The box-whisker plots were used to express the drug dosing recommendations in cirrhosis patients (CP-A-C). For this purpose, AUC unbound and AUC total of the propranolol in healthy and diseased populations (CP-A-C) were determined.…”

Considerations in the extrapolation of drug toxicity between humans and dogs

“…However, the amount of available information increases as the product progresses through the different stages of development. PBPK platforms, combined with IVIVE techniques, are positioned to incorporate and utilize these experimental data as they become available [65]. In so doing, the PBPK models can greatly enhance the information derived from that early…”