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


Equipe mixte de recherche 3738, Ciblage Thérapeutique en Oncologie, Faculté de Médecine et de Maïeutique Lyon-Sud Charles Mérieux, Université Claude Bernard Lyon 1, Oullins, France (P.P., E.H., M.T.); Pharmacie Hôpital de la Croix Rousse, Hospices Civils de Lyon, Lyon, France (M.T.); Centre de Pharmacocinétique et Métabolisme, Technologie Servier, Orléans, France (P.P., F.B.); Clinical Pharmacokinetics and Pharmacometrics Division, Servier, Suresnes, France (K.B., J.O., M.A., M.C.); and Institut de Recherches Internationales Servier, Oncology R&D Unit, Suresnes, France (L.K-B.) [Email]


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 (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.

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