Translational approach from preclinical to clinical: comparison of dose finding methods of a new Bcl2 inhibitor using PK
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PHASE I STUDIES
Translational approach from preclinical to clinical: comparison of dose finding methods of a new Bcl2 inhibitor using PK-PD modeling and interspecies extrapolation Philippe B. Pierrillas 1,2,3 & Emilie Henin 1,4 & Julien Ogier 5,6 & Magali Amiel 5 & Laurence Kraus-Berthier 7 & Marylore Chenel 5 & François Bouzom 2,8 & Michel Tod 1,9 Received: 14 March 2020 / Accepted: 18 May 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Summary The attrition rate of anticancer drugs during the clinical development remains very high. Interspecies extrapolation of anticancer drug pharmacodynamics (PD) could help to bridge the gap between preclinical and clinical settings and to improve drug development. Indeed, when combined with a physiologically-based-pharmacokinetics (PBPK) approach, PD interspecies extrapolation could be a powerful tool for predicting drug behavior in clinical trials. The present study aimed to explore this field for anticipating the clinical efficacy of a new Bcl-2 inhibitor, S 55746, for which dose ranging studies in xenografted mice and clinical data from a phase 1 trial involving cancer patients were available. Different strategies based on empirical or more mechanistic assumptions (based on PBPK-PD modelling) were developped and compared: the Rocchetti approach (ROC); the Orthogonal Rocchetti approach (oROC), a variant of ROC based on an orthogonal regression; the Consistent across species approach, bringing out an efficacy parameter assumed to be consistent across species; and the Scaling species-specific parameters approach, assuming the concentration-efficacy link is the same in mice as in humans, after allometric scaling. Empirical approaches (ROC and oROC) gave similar predictive performances and seemed to overestimate the active S 55746 dose compared to mechanistic approaches, while strategies elaborated from semi-mechanistic concepts and PBPK-PD modelling did not seem to be invalidated by clinical efficacy data. Also, empirical methods only predict a single dose level for the subsequent clinical studies, whereas mechanism-based strategies are more informative about the dose response relationship, highlighting the potential interest of such approaches in drug development. Keywords Oncology . Physiologically based pharmacokinetics – pharmacodynamics . Pharmacometrics . Interspecies extrapolation strategies
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10637-020-00953-y) contains supplementary material, which is available to authorized users. * Philippe B. Pierrillas [email protected] 1
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Clinical Pharmacokinetics and Pharmacometrics Division, Servier, Paris, France
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Present address: Translational DMPK & Safety, IPSEN Innovation 5 avenue du Canada, ZI Courtaboeuf, Les Ulis, France
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Centre de Pharmacocinétique et Métabolisme, Technologie Servier, Orléans, France
Institut de Recherches Internationales Servier, Oncology R&D Unit, Suresnes, France
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Faculté de Médecine & Maïeutique
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