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Absorption, Distribution, Metabolism, and Excretion (ADME) of Capmatinib (INC280) in Healthy Male Volunteers and In Vitro Aldehyde Oxidase Phenotyping of the Major Metabolite

Glaenzel, Ulrike and Jin, Yi and Hansen, Regine and Schroer, Kirsten and Rahmanzadeh, Gholamreza and Pfaar, Ulrike and van Lier, Jan Jaap and Borell, Hubert and Meissner, Axel and Camenisch, Gian P. and Zhao, Sylvia (2020) Absorption, Distribution, Metabolism, and Excretion (ADME) of Capmatinib (INC280) in Healthy Male Volunteers and In Vitro Aldehyde Oxidase Phenotyping of the Major Metabolite. Drug Metabolism and Disposition, 48 (10). pp. 873-885. ISSN 0090-95561521-009X

Abstract

Capmatinib (INC280), a highly selective and potent inhibitor of the MET receptor tyrosine kinase, has demonstrated clinically meaningful efficacy and a manageable safety profile in patients with advanced NSCLC harboring MET exon 14 skipping mutations. We investigated the absorption, distribution, metabolism, and excretion of capmatinib in six healthy male volunteers after a single peroral dose of 600 mg 14C-labeled capmatinib. The mass balance, blood and plasma radioactivity, and plasma capmatinib concentrations were determined along with metabolite profiles in plasma, urine, and feces. The metabolite structures were elucidated using mass spectrometry and comparing with reference compounds. The parent compound accounted for most of the radioactivity in plasma (42.9 ± 2.9%). The extent of oral absorption was estimated to be 49.6%; the maximum concentration (Cmax) of capmatinib in plasma was reached at 2 h (median Tmax). The apparent mean elimination half-life of capmatinib in plasma was 7.84 h. Apparent distribution volume (Vz/F) of capmatinib during the terminal phase was moderate to high (geometric mean 473 L). Metabolic reactions involved lactam formation, hydroxylation, N-dealkylation, formation of a carboxylic acid, hydrogenation, N oxygenation, glucuronidation, and combinations thereof. The most abundant metabolite, M16 was formed by imidazo-triazinone formation (lactam formation). Absorbed capmatinib was eliminated mainly by metabolism and subsequent biliary/fecal and renal excretion. Excretion of radioactivity was complete after 7 days. In vitro studies demonstrated that CYP3A was the major P450 enzyme subfamily involved in hepatic microsomal metabolism, and M16 formation was mainly catalyzed by cytosol aldehyde oxidase.

Item Type: Article
Keywords: absorption, distribution, metabolism, excretion, ADME, mass balance, capmatinib, systemic availability, metabolized, elimination, metabolite, aldehyde oxidase, CYP3A, hepatic microsomal metabolism, 14C-labelled
Date Deposited: 29 Dec 2020 00:45
Last Modified: 29 Dec 2020 00:45
URI: https://oak.novartis.com/id/eprint/42217

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