Open-label, single-center, phase I trial to investigate the mass balance and absolute bioavailability of the highly sele
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PHASE I STUDIES
Open-label, single-center, phase I trial to investigate the mass balance and absolute bioavailability of the highly selective oral MET inhibitor tepotinib in healthy volunteers Andreas Johne 1 & Holger Scheible 2 & Andreas Becker 1 & Jan Jaap van Lier 3 & Peter Wolna 1 & Michael Meyring 2 Received: 24 January 2020 / Accepted: 16 March 2020 # The Author(s) 2020
Summary Tepotinib (MSC2156119J) is an oral, potent, highly selective MET inhibitor. This open-label, phase I study in healthy volunteers (EudraCT 2013-003226-86) investigated its mass balance (part A) and absolute bioavailability (part B). In part A, six participants received tepotinib orally (498 mg spiked with 2.67 MBq [14C]-tepotinib). Blood, plasma, urine, and feces were collected up to day 25 or until excretion of radioactivity was 1000-fold selectivity for MET over 236 out of 241 other kinases tested, and >200-fold selectivity over the other five [8]. In the first-in-man trial, tepotinib doses of up to 1400 mg/ day were administered in patients with solid tumors without reaching the maximum tolerated dose; 500 mg once daily was subsequently established as the recommended phase II dose
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(RP2D) based on a translational modeling approach [9]. Tepotinib alone or in combination has been shown to be active in various preclinical tumor models [8, 10–16]. It is currently being studied in clinical trials involving patients with hepatocellular carcinoma (NCT01988493, NCT02115373) [17, 18] and NSCLC (NCT01982955, NCT02864992, NCT03940703) [16, 19–22]. The purpose of the present study (EudraCT 2013-00322686) was the characterization of the pharmacokinetics (PK), drug disposition, and metabolism of tepotinib in healthy volunteers. In part A of the study, [14C]-tepotinib was administered orally to evaluate the absorption, distribution, metabolism, and excretion of tepotinib. The availability of [14C]-labeled tepotinib, in conjunction with recent advances in the clinical use of microtracer doses and ultrasensitive bioanalytical methods [23], allowed the evaluation of the PK of tepotinib after intravenous (IV) dosing and its absolute bioavailability in part B of this study. For orally administered drugs such as tepotinib, characterization of the PK profile following IV dosing is of highest value for correct interpretation of distribution and elimination [24]. The combination of both investigations (mass balance and absolute bioavailability) in this study represented an opportunity to obtain a comprehensive understanding of the PK of tepotinib, supporting the ongoing formulation development and its phase II program.
Materials and methods Study design This was an open-label, single-center, phase I study in two parts, designed to investigate the mass balance, metabolism, and absolute bioavailability of tepotinib in two groups of six healthy male volunteers (EudraCT 2013-003226-86). Part A of the study was designed to evaluate the mass balance of tepotinib, identify major routes of elimination, determine the unbound fraction of tepotin
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