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J Pharmacol Exp Ther. 2018 Dec;367(3):414-424. doi: 10.1124/jpet.118.251694. Epub 2018 Sep 18.

Tumor Growth Inhibition Modelling Based on Receptor Occupancy and Biomarker Activity of a New Bcl-2 Inhibitor in Mice.

Author information

1
EMR 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., J.O., F.B.); Clinical Pharmacokinetics and Pharmacometrics Division, Servier, Paris, France (M.C.); and Institut de Recherches Internationales Servier, Oncology R&D Unit, Suresnes, France (L.K-B.) philippe.pierrillas@gmail.com.
2
EMR 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., J.O., F.B.); Clinical Pharmacokinetics and Pharmacometrics Division, Servier, Paris, France (M.C.); and Institut de Recherches Internationales Servier, Oncology R&D Unit, Suresnes, France (L.K-B.).

Abstract

The Bcl-2 inhibitor 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 able to restore apoptosis functions impaired by tumorigenesis in mice. Data from pharmacokinetic (PK), biomarker, and tumor growth studies in a xenograft mouse model were considered for population modeling. The aim of the modeling exercise was to link the kinetics of the drug to the biomarker and tumor-size time profiles to better understand its dose-effect relationship. The PK, caspase kinetics, and tumor dynamics were successfully characterized by the proposed pharmacokinetic-pharmacodynamic model. The nonlinear plasma PK was best described by a two-compartment disposition model with both saturable absorption and elimination. Caspase was activated above the effective drug-concentration threshold (CTHRE ), at which near-maximal activity was reached. Increasing the dose did not increase the activation but better sustained it. Tumor growth followed a biphasic pattern, with caspase having an all-or-none inhibiting effect, consistent with the bistability property of the caspase pathway. For tumor eradication, the CTHRE in plasma was 2876 ng ml-1, and the relative caspase activity threshold (CaspTHRE) was 46.5. There was a strong relationship between the time spent above these thresholds and tumor growth inhibition. Tumor growth was inhibited by 50% when CaspTHRE was exceeded 13.8% of the time and when CTHRE was exceeded 8.1% of the time per dosing. This semimechanistic approach, based on experimental mice data and in vitro parameters, provides an interesting tool to quantify or simulate antitumor effects and, eventually, to plan phase 1 studies.

PMID:
30228112
DOI:
10.1124/jpet.118.251694
[Indexed for MEDLINE]

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