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Research ArticleDrug Discovery and Translational Medicine

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

Philippe B. Pierrillas, Emilie Henin, Julien Ogier, Laurence Kraus-Berthier, Marylore Chenel, François Bouzom and Michel Tod
Journal of Pharmacology and Experimental Therapeutics December 2018, 367 (3) 414-424; DOI: https://doi.org/10.1124/jpet.118.251694
Philippe B. Pierrillas
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.)
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Emilie Henin
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.)
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Julien Ogier
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.)
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Laurence Kraus-Berthier
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.)
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Marylore Chenel
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.)
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François Bouzom
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.)
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Michel Tod
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.)
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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.

Footnotes

    • Received June 30, 2018.
    • Accepted September 10, 2018.
  • ↵1 Current affiliation: Calvagone, Liergues, France.

  • ↵2 Current affiliation: Translational DMPK & Safety, IPSEN Innovation, ZI Courtaboeuf, Les Ulis, France.

  • ↵3 Current affiliation: UCB Biopharma, Development Sciences, Braine l’Alleud, Belgium.

  • E.H. was funded by Fondation Synergie Lyon Cancer and La Ligue Nationale contre le Cancer. This work is part of a Ph.D. project (P.P.) granted by Servier Laboratories.

  • https://doi.org/10.1124/jpet.118.251694.

  • ↵Embedded ImageThis article has supplemental material available at jpet.aspetjournals.org.

  • Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 367 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 367, Issue 3
1 Dec 2018
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Research ArticleDrug Discovery and Translational Medicine

Tumor Growth Inhibitory Model of a Bcl-2 Inhibitor in Mice

Philippe B. Pierrillas, Emilie Henin, Julien Ogier, Laurence Kraus-Berthier, Marylore Chenel, François Bouzom and Michel Tod
Journal of Pharmacology and Experimental Therapeutics December 1, 2018, 367 (3) 414-424; DOI: https://doi.org/10.1124/jpet.118.251694

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Research ArticleDrug Discovery and Translational Medicine

Tumor Growth Inhibitory Model of a Bcl-2 Inhibitor in Mice

Philippe B. Pierrillas, Emilie Henin, Julien Ogier, Laurence Kraus-Berthier, Marylore Chenel, François Bouzom and Michel Tod
Journal of Pharmacology and Experimental Therapeutics December 1, 2018, 367 (3) 414-424; DOI: https://doi.org/10.1124/jpet.118.251694
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