1. Tumor Growth Inhibition Modelling Based on Receptor Occupancy and Biomarker Activity of a New Bcl-2 Inhibitor in Mice
- Author
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Philippe B. Pierrillas, Marylore Chenel, Michel Tod, Emilie Henin, Laurence Kraus-Berthier, François Bouzom, and Julien Ogier
- Subjects
Population ,Antineoplastic Agents ,Pharmacology ,medicine.disease_cause ,Models, Biological ,030226 pharmacology & pharmacy ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Pharmacokinetics ,Biomarkers, Tumor ,medicine ,Animals ,education ,Receptor ,Caspase ,Cell Proliferation ,education.field_of_study ,biology ,Chemistry ,Xenograft Model Antitumor Assays ,In vitro ,Disease Models, Animal ,Proto-Oncogene Proteins c-bcl-2 ,Apoptosis ,Caspases ,030220 oncology & carcinogenesis ,biology.protein ,Molecular Medicine ,Biomarker (medicine) ,Carcinogenesis - 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.
- Published
- 2018