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

Abstract

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 [ 14 C]-tepotinib). Blood, plasma, urine, and feces were collected up to day 25 or until excretion of radioactivity was <1% of the administered dose. In part B, six participants received 500 mg tepotinib orally as a film-coated tablet, followed by an intravenous [ 14 C]-tepotinib tracer dose (53-54 kBq) 4 h later. Blood samples were collected until day 14. In part A, a median of 92.5% (range, 87.1-96.9%) of the [ 14 C]-tepotinib dose was recovered in excreta. Radioactivity was mainly excreted via feces (median, 78.7%; range, 69.4-82.5%). Urinary excretion was a minor route of elimination (median, 14.4% [8.8-17.7%]). Parent compound was the main constituent in excreta (45% [feces] and 7% [urine] of the radioactive dose). M506 was the only major metabolite. In part B, absolute bioavailability was 72% (range, 62-81%) after oral administration of 500 mg tablets (the dose and formulation used in phase II trials). In conclusion, tepotinib and its metabolites are mainly excreted via feces; parent drug is the major eliminated constituent. Oral bioavailability of tepotinib is high, supporting the use of the current tablet formulation in clinical trials. Tepotinib was well tolerated in this study with healthy volunteers.

Tepotinib Inhibits Several Drug Efflux Transporters and Biotransformation Enzymes: The Role in Drug-Drug Interactions and Targeting Cytostatic Resistance In Vitro and Ex Vivo

“…First, we described inhibition of several ABC drug efflux transporters and CYP isozymes by tepotinib. However, considering tepotinib’s steady state C max observed at recommended dosing of 500 mg daily (2.62 µM) [ 11 ], unbound fraction (up to 3.25% of a dose) [ 12 ] and FDA/EMA guidelines [ 10 , 13 ], only ABCB1 and CYP2C9 inhibitions can be considered potentially clinically relevant for perpetrating systemic pharmacokinetic DIs. This statement is in accordance with the results of DI study in healthy subjects, where tepotinib significantly increased AUC and C max of DI-sensitive ABCB1 substrate dabigatran etexilate, but it failed to exert the effect on CYP3A4 substrate midazolam [ 14 ].…”

SHP2 Inhibition Influences Therapeutic Response to Tepotinib in Tumors with MET Alterations

“…Thus, MET is an attractive target in NSCLC and MET targeted therapies have demonstrated efficacy in lung tumors with MET alterations ( Koch et al., 2020 ). Tepotinib is an oral, potent, highly selective MET inhibitor ( Johne et al., 2020 ) that has been approved in Japan for the treatment of patients with unresectable, advanced, or recurrent NSCLC with METex14 skipping alterations ( Paik et al., 2020 ), whereas it is under clinical investigation in combination with EGFR TKIs for patients with EGFR-mutant lung adenocarcinomas and MET amplification as an acquired resistance mechanism ( NCT03940703 ). The present work provides molecular evidence that resistance to tepotinib is mediated by bypass signaling via other RTKs and the activation of downstream signaling nodes.…”

Translational pharmacokinetic‐pharmacodynamic modeling of preclinical and clinical data of the oral MET inhibitor tepotinib to determine the recommended phase II dose

“…For oral administration in animal studies, the compounds were prepared as described in the Supplementary Methods. MSC2571109A is the R‐enantiomer of the oxidative metabolite of tepotinib, which was first identified in a human mass balance trial 31 . MSC2571109A represents 65% of parent exposure; however, it is not formed in mice.…”