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

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 non-small-cell lung cancer 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 14 C-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% 6 2.9%). The extent of oral absorption was estimated to be 49.6%; the C max of capmatinib in plasma was reached at 2 hours (median time to reach C max). The apparent mean elimination half-life of capmatinib in plasma was 7.84 hours. Apparent distribution volume 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. M16, the most abundant metabolite in plasma, urine, and feces was formed by lactam formation. Absorbed capmatinib was eliminated mainly by metabolism and subsequent biliary/fecal and renal excretion. Excretion of radioactivity was complete after 7 days. CYP phenotyping demonstrated that CYP3A was the major cytochrome P450 enzyme subfamily involved in hepatic microsomal metabolism, and in vitro studies in hepatic cytosol indicated that M16 formation was mainly catalyzed by aldehyde oxidase. SIGNIFICANCE STATEMENT The absorption, distribution, metabolism, and excretion of capmatinib revealed that capmatinib had substantial systemic availability after oral administration. It was also extensively metabolized and largely distributed to the peripheral tissue. Mean elimination half-life was 7.84 hours. The most abundant metabolite, M16, was formed by imidazo-triazinone formation catalyzed by cytosolic aldehyde oxidase. Correlation analysis, specific inhibition, and recombinant enzymes phenotyping demonstrated that CYP3A is the major enzyme subfamily involved in the hepatic microsomal metabolism of [ 14 C]capmatinib.

Comparison of Tissue Abundance of Non-Cytochrome P450 Drug-Metabolizing Enzymes by Quantitative Proteomics between Humans and Laboratory Animal Species

“…For example, both SGX523 and JNJ-38877605 (Lolkema et al, 2015) were responsible for nephrotoxicity due to the formation of insoluble metabolites mediated by AOX in human kidney and ultimately leading to discontinuation as a clinical candidate. Capmatinib, a highly selective and potent MET (tyrosine kinase receptor) inhibitor also failed due to high interspecies differences in its AOX mediated metabolism and toxicity (Lolkema et al, 2015;Glaenzel et al, 2020). Considering the implications of interspecies differences in drug development, here we provided a quantitative comparison of non-CYP enzymes in humans versus the non-human primates (cynomolgus and rhesus), dog, rat, and mouse.…”

Pharmacokinetics and safety of capmatinib with food in patients with MET-dysregulated advanced solid tumors

“…Capmatinib plasma concentrations were determined by using a validated LC-MS/MS assay, which has been described elsewhere. 35 The assay used a lower limit of quantitation of ˜1 ng/mL using 100 μL of plasma sample in di-potassium EDTA. Sample preparation in 96-well plates comprised addition of a 100 μL aliquot of the samples, a 50 μL aliquot of the internal standard working solution, and a 300 μL aliquot of 0.5% ammonium hydroxide solution to the designated wells.…”

“…34 In an absorption, distribution, metabolism, and excretion study in healthy male volunteers, 14 Clabeled capmatinib (a single 600 mg oral dose, capsule formulation) had substantial systemic availability, was extensively metabolized, and was mainly distributed to the peripheral tissue, with a mean elimination t 1/2 of 7.84 hours. 35 The highest tested dose of capmatinib in tablet formulation reported in the literature is 400 mg BID, 13 , 32 , 36 and all published pharmacokinetic (PK) studies have been conducted under fasted conditions.…”

Management of Peripheral Edema in Patients with MET Exon 14-Mutated Non-small Cell Lung Cancer Treated with Small Molecule MET Inhibitors

“…The perturbation of the HGF/MET signaling by the inhibition of MET could disrupt the permeability balance in the vascular endothelium [ 36 ], thus, promoting edema development. A study in healthy volunteers treated with capmatinib showed that the drug was largely distributed to the peripheral tissues [ 37 ], which could contribute to the development of peripheral edema in patients treated with MET inhibitors.…”