Population pharmacokinetics of ATR inhibitor berzosertib in phase I studies for different cancer types
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ORIGINAL ARTICLE
Population pharmacokinetics of ATR inhibitor berzosertib in phase I studies for different cancer types Nadia Terranova1 · Mendel Jansen2 · Martin Falk3 · Bart S. Hendriks4 Received: 30 April 2020 / Accepted: 14 October 2020 © The Author(s) 2020
Abstract Purpose Berzosertib (formerly M6620) is the first-in-class inhibitor of ataxia–telangiectasia and Rad3-related protein, a key component of the DNA damage response, and being developed in combination with chemotherapy for the treatment of patients with advanced cancers. The objectives of this analysis were to characterize the pharmacokinetics (PK) of berzosertib across multiple studies and parts, estimate inter-individual variability, and identify covariates that could explain such variability. Methods A population PK analysis was performed using the combined dataset from two phase I clinical studies (NCT02157792, EudraCT 2013-005100-34) in patients with advanced cancers receiving an intravenous infusion of berzosertib alone or in combination with chemotherapy. The analysis included data from 240 patients across 11 dose levels (18–480 mg/m2). Plasma concentration data were modeled with a non-linear mixed-effect approach and clinical covariates were evaluated. Results PK data were best described by a two-compartment linear model. For a typical patient, the estimated clearance (CL) and intercompartmental CL were 65 L/h and 295 L/h, respectively, with central and peripheral volumes estimated to be 118 L and 1030 L, respectively. Several intrinsic factors were found to influence berzosertib PK, but none were considered clinically meaningful due to a very limited effect. Model simulations indicated that concentrations of berzosertib exceeded p-Chk1 (proximal pharmacodynamic biomarker) I C50 at recommended phase II doses in combination with carboplatin, cisplatin, and gemcitabine. Conclusions There was no evidence of a clinically significant PK interaction between berzosertib and evaluated chemocombinations. The covariate analysis did not highlight any need for dosing adjustments in the population studied to date. Clinical Trial information NCT02157792, EudraCT 2013-005100-34 Keywords ATR inhibitor · Berzosertib · Population pharmacokinetics · DNA damage repair (DDR) inhibitors
Introduction Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00280-020-04184-z) contains supplementary material, which is available to authorized users. * Nadia Terranova [email protected] 1
Translational Medicine, Merck Institute of Pharmacometrics, Lausanne, Switzerland, an affiliate of Merck KGaA, Darmstadt, Germany
2
Clinical Pharmacology, QureQuest Ltd, London, UK
3
Global Clinical Development, Merck KGaA, Darmstadt, Germany
4
Translational Medicine, EMD Serono Research & Development Institute, Inc. (an affiliate of Merck KGaA, Darmstadt, Germany), Billerica, MA, USA
Berzosertib (formerly M6620, VX-970, VE-822) is a selective and potent inhibitor of ataxia–telangiectasia and Rad3related
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