Abstract
SummaryTepotinib (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.
Highlights
The mesenchymal–epithelial transition (MET) factor is a receptor tyrosine kinase with a single high-affinity ligand, hepatocyte growth factor (HGF) [1]
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)
726.0 (24.8), 550.0–969.4 a Values are geometric mean, followed by min–max, except for tmax and tlag, for which median values, followed by min–max, are provided b To allow comparisons in this table, exposure parameters Cmax, AUC0–t, and AUC0–∞ estimated after IV tracer administration were individually adjusted to the 500 mg oral dose, including a factor to normalize for salt:free base concentration
Summary
The mesenchymal–epithelial transition (MET) factor is a receptor tyrosine kinase with a single high-affinity ligand, hepatocyte growth factor (HGF) [1]. Oncogenic MET may initiate or promote tumorigenesis, but may drive resistance to other therapies [2, 3]. Exon 14 skipping and high-level amplification of MET are considered primary tumor-driving alterations in non-small cell lung cancer (NSCLC) [2, 4]. MET amplification is recognized as a secondary oncogenic driver alteration mediating resistance to epidermal growth factor receptor inhibition [2, 5]. Several inhibitors of the MET pathway are currently in development as potential antitumor therapies [2, 3, 6, 7]. 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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