In vitro and in vivo pharmacokinetic characterization of mavacamten, a first-in-class small molecule allosteric modulator of beta cardiac myosin
| Autor: | Marc J. Evanchik, Priscilla Brun, John C L Erve, Nicole V Haste, Mark P. Grillo, Svetlana Markova, Ryan Dick, Timothy J. Carlson, James P Driscoll |
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| Rok vydání: | 2018 |
| Předmět: |
Male
Benzylamines Allosteric modulator Metabolic Clearance Rate Health Toxicology and Mutagenesis Pharmacology Toxicology 030226 pharmacology & pharmacy Biochemistry Rats Sprague-Dawley 03 medical and health sciences 0302 clinical medicine Dogs Pharmacokinetics Cytochrome P-450 Enzyme System In vivo medicine Animals Humans Drug Interactions Beta (finance) Uracil Mice Inbred ICR Chemistry Hypertrophic cardiomyopathy General Medicine Cardiomyopathy Hypertrophic medicine.disease Small molecule In vitro Macaca fascicularis 030220 oncology & carcinogenesis Hepatocytes Microsomes Liver Caco-2 Cells Cardiac Myosins Drug metabolism |
| Zdroj: | Xenobiotica; the fate of foreign compounds in biological systems. 49(6) |
| ISSN: | 1366-5928 |
| Popis: | Mavacamten is a small molecule modulator of cardiac myosin designed as an orally administered drug for the treatment of patients with hypertrophic cardiomyopathy. The current study objectives were to assess the preclinical pharmacokinetics of mavacamten for the prediction of human dosing and to establish the potential need for clinical pharmacokinetic studies characterizing drug–drug interaction potential.Mavacamten does not inhibit CYP enzymes, but at high concentrations relative to anticipated therapeutic concentrations induces CYP2B6 and CYP3A4 enzymes in vitro. Mavacamten showed high permeability and low efflux transport across Caco-2 cell membranes. In human hepatocytes, mavacamten was not a substrate for drug transporters OATP, OCT and NTCP. Mavacamten was determined to have minimal drug–drug interaction risk.In vitro mavacamten metabolite profiles included phase I- and phase II-mediated metabolism cross-species. Major pathways included aromatic hydroxylation (M1), aliphatic hydroxylation (M2); N-dealkylation (M6), and glucuronidation of the M1-metabolite (M4). Reaction phenotyping revealed CYPs 2C19 and 3A4/3A5 predominating.Mavacamten demonstrated low clearance, high volume of distribution, long terminal elimination half-life and excellent oral bioavailability cross-species.Simple four-species allometric scaling led to predicted plasma clearance, volume of distribution and half-life of 0.51 mL/min/kg, 9.5 L/kg and 9 days, respectively, in human. Mavacamten is a small molecule modulator of cardiac myosin designed as an orally administered drug for the treatment of patients with hypertrophic cardiomyopathy. The current study objectives were to assess the preclinical pharmacokinetics of mavacamten for the prediction of human dosing and to establish the potential need for clinical pharmacokinetic studies characterizing drug–drug interaction potential. Mavacamten does not inhibit CYP enzymes, but at high concentrations relative to anticipated therapeutic concentrations induces CYP2B6 and CYP3A4 enzymes in vitro. Mavacamten showed high permeability and low efflux transport across Caco-2 cell membranes. In human hepatocytes, mavacamten was not a substrate for drug transporters OATP, OCT and NTCP. Mavacamten was determined to have minimal drug–drug interaction risk. In vitro mavacamten metabolite profiles included phase I- and phase II-mediated metabolism cross-species. Major pathways included aromatic hydroxylation (M1), aliphatic hydroxylation (M2); N-dealkylation (M6), and glucuronidation of the M1-metabolite (M4). Reaction phenotyping revealed CYPs 2C19 and 3A4/3A5 predominating. Mavacamten demonstrated low clearance, high volume of distribution, long terminal elimination half-life and excellent oral bioavailability cross-species. Simple four-species allometric scaling led to predicted plasma clearance, volume of distribution and half-life of 0.51 mL/min/kg, 9.5 L/kg and 9 days, respectively, in human. |
| Databáze: | OpenAIRE |
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