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 [¹⁴C]-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 [¹⁴C]-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 [¹⁴C]-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.

Keywords: Bioavailability; Mass balance; Metabolites; Pharmacokinetics; Tepotinib; Tyrosine kinase inhibitor.

Fig. 1

Median cumulative recovery of [¹⁴C]-radioactivity in urine and feces and combined (total). Pie chart shows respective geometric mean values

Fig. 2

Mean plasma concentration–time curve for tepotinib and total radioactivity (linear scale [top panel] and log-linear scale [bottom panel]) (n = 6)

Fig. 3

Proposed metabolic pathway for tepotinib. Structural formulae are postulates and have yet to be confirmed by nuclear magnetic resonance analysis and/or chemical synthesis, except for those proven by synthesis: racemic M506 (MSC2569775), M508–1 (MSC2489309), M508–2 (MSC2489308), and M478 (MSC2157042)

Fig. 4

Mean plasma concentration–time curves for tepotinib after oral and IV administration (log-linear scale)