RT Journal Article SR Electronic T1 Prediction of human nonlinear pharmacokinetics of a new Bcl-2 inhibitor using PBPK modelling and interspecies extrapolation strategy JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP dmd.118.085605 DO 10.1124/dmd.118.085605 A1 Philippe B. Pierrillas A1 Emilie Henin A1 Kathryn Ball A1 Julien Ogier A1 Magali Amiel A1 Laurence Kraus-Berthier A1 Marylore Chenel A1 Francois Bouzom A1 Michel Tod YR 2019 UL http://dmd.aspetjournals.org/content/early/2019/04/02/dmd.118.085605.abstract AB S 55746 ((S)-N-(4-hydroxyphenyl)-3-(6-(3-(morpholinomethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzo[d][1,3]dioxol-5-yl)-N-phenyl-5,6,7,8-tetrahydroindolizine-1-carboxamide) is a new selective Bcl-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 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 to 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 8 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 physiological assumptions, could be a useful tool for predicting human plasma concentrations at the early stage of drug development.