Assessment of the potential of the MET inhibitor tepotinib to affect the pharmacokinetics of CYP3A4 and P-gp substrates.

Autor: Yalkinoglu Ö; Clinical Pharmacology, Quantitative Pharmacology, the healthcare business of Merck KGaA, Darmstadt, Germany., Becker A; Clinical Pharmacology, Quantitative Pharmacology, the healthcare business of Merck KGaA, Darmstadt, Germany., Krebs-Brown A; Global Biostatistics, Epidemiology and Medical Writing, the healthcare business of Merck KGaA, Darmstadt, Germany., Vetter C; Clinical Pharmacology, Quantitative Pharmacology, the healthcare business of Merck KGaA, Darmstadt, Germany., Lüpfert C; Clinical Pharmacology, Quantitative Pharmacology, the healthcare business of Merck KGaA, Darmstadt, Germany., Perrin D; NCE DMPK, Discovery and Development Technologies, the healthcare business of Merck KGaA, Darmstadt, Germany., Heuer J; Clinical Services, Nuvisan GmbH, Neu-Ulm, Germany., Biedert H; LC/MS Bioanalysis, Nuvisan GmbH, Neu-Ulm, Germany., Hirt S; LC/MS Bioanalysis, Nuvisan GmbH, Neu-Ulm, Germany., Bytyqi A; Clinical Pharmacology, Quantitative Pharmacology, the healthcare business of Merck KGaA, Darmstadt, Germany., Bachmann A; Clinical Pharmacology, Quantitative Pharmacology, the healthcare business of Merck KGaA, Darmstadt, Germany., Strotmann R; Clinical Pharmacology, Quantitative Pharmacology, the healthcare business of Merck KGaA, Darmstadt, Germany. Rainer.Strotmann@emdserono.com.
Jazyk: angličtina
Zdroj: Investigational new drugs [Invest New Drugs] 2023 Aug; Vol. 41 (4), pp. 596-605. Date of Electronic Publication: 2023 Jul 06.
DOI: 10.1007/s10637-023-01378-z
Abstrakt: Tepotinib is a highly selective, potent, mesenchymal-epithelial transition factor (MET) inhibitor, approved for the treatment of non-small cell lung cancer harboring MET exon 14 skipping alterations. The aims of this work were to investigate the potential for drug-drug interactions via cytochrome P450 (CYP) 3A4/5 or P-glycoprotein (P-gp) inhibition. In vitro studies were conducted in human liver microsomes, human hepatocyte cultures and Caco-2 cell monolayers to investigate whether tepotinib or its major metabolite (MSC2571109A) inhibited or induced CYP3A4/5 or inhibited P-gp. Two clinical studies were conducted to investigate the effect of multiple dose tepotinib (500 mg once daily orally) on the single dose pharmacokinetics of a sensitive CYP3A4 substrate (midazolam 7.5 mg orally) and a P-gp substrate (dabigatran etexilate 75 mg orally) in healthy participants. Tepotinib and MSC2571109A showed little evidence of direct or time-dependent CYP3A4/5 inhibition (IC 50  > 15 μM) in vitro, although MSC2571109A did show mechanism-based CYP3A4/5 inhibition. Tepotinib did not induce CYP3A4/5 activity in vitro, although both tepotinib and MSC2571109A increased CYP3A4 mRNA. In clinical studies, tepotinib had no effect on the pharmacokinetics of midazolam or its metabolite 1'-hydroxymidazolam. Tepotinib increased dabigatran maximum concentration and area under the curve extrapolated to infinity by 38% and 51%, respectively. These changes were not considered to be clinically relevant. Tepotinib was considered safe and well tolerated in both studies. The potential of tepotinib to cause clinically relevant DDI with CYP3A4- or P-gp-dependent drugs at the clinical dose is considered low. Study 1 (midazolam): NCT03628339 (registered 14 August 2018). Study 2 (dabigatran): NCT03492437 (registered 10 April 2018).
(© 2023. The Author(s).)
Databáze: MEDLINE
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