Pharmacokinetics, disposition, and biotransformation of the cardiac myosin inhibitor aficamten in humans

Pharmacokinetics, disposition, and biotransformation of the cardiac myosin inhibitor aficamten in humans

Aficamten, a cardiac myosin inhibitor, is being developed for the treatment of patients with symptomatic hypertrophic cardiomyopathy (HCM). The purpose of this study was to determine the absorption, metabolism, and excretion of aficamten. Eight healthy male participants received a single oral dose o...

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Bibliographic Details
Published in:Pharmacology research & perspectives Vol. 12; no. 5; pp. e70006 - n/a
Main Authors: Xu, Donghong, Divanji, Punag, Griffith, Adrienne, Sukhun, Rajaa, Cheplo, Kathleen, Li, Jianlin, German, Polina
Format: Journal Article
Language:English
Published: United States John Wiley & Sons, Inc 01-10-2024
John Wiley and Sons Inc
Wiley
Subjects:
absorption
Administration, Oral
Adult
aficamten
Biotransformation
Body mass index
Cardiac Myosins - metabolism
Cardiomyopathy
Chromatography
Cytochrome
distribution
Dosimetry
Drug dosages
Ejection fraction
Electrocardiography
excretion
Feces
Feces - chemistry
Healthy Volunteers
Humans
Male
Mass spectrometry
metabolism
Metabolites
Middle Aged
Original
Pharmacokinetics
Plasma
Radioactivity
Scientific imaging
Urine
Young Adult
biotransformation
excretion
absorption
pharmacokinetics
metabolism
aficamten
distribution
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Summary:Aficamten, a cardiac myosin inhibitor, is being developed for the treatment of patients with symptomatic hypertrophic cardiomyopathy (HCM). The purpose of this study was to determine the absorption, metabolism, and excretion of aficamten. Eight healthy male participants received a single oral dose of 20 mg aficamten (containing approximately 100 μCi of radiocarbon). Blood, urine, and feces samples were collected up to a maximum of Day 26. The pharmacokinetics of aficamten were characterized by moderate absorption, with a median tmax of 2.0 h postdose. The median t1/2 of aficamten was 99.6 h with similar t1/2 observed for metabolites and total radioactivity in plasma and whole blood. The overall total recovery of administered total radioactivity was 89.7% with 57.7% of the dose recovered in feces and 32.0% in urine. The main circulating metabolites in plasma included monohydroxylated metabolites M1a (CK‐3834282) and M1b (CK‐3834283) accounting for 10.5% and 36.4% of the total radioactivity AUC both with a median tmax of 5 h. The other major plasma metabolite was M5 (an oxygen‐linked glucuronide conjugate of M1a), which accounted for 10.3% of the total plasma radioactivity exposure, with a tmax of 24 h. In urine, M5 was the most abundant metabolite with 8.02% total radioactive dose (TRD), followed by M1a and M1b with 6.16% and 2.85% TRD, respectively; however, there were no metabolites in urine observed at >10% of dose. The major metabolite in feces was M18 representing 44.1% of the radioactive dose. These findings indicated that aficamten was eliminated by metabolism, and to a minor extent, by fecal excretion of unchanged aficamten with renal excretion playing a minor role. Feces were the principal route of excretion of the radioactive dose. Proposed biotransformation pathways of aficamten in male humans.
Bibliography:Previous Presentations: Xu D, Divanji P, Cheplo K, Li, J, German P. 2023. Disposition and Metabolism of the Cardiac Myosin Inhibitor Aficamten in Humans. Proceedings of a symposium held at the American Association of Pharmaceutical Scientists. 2023, October 22–25; Orlando, FL, United States.
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ISSN:2052-1707
2052-1707
DOI:10.1002/prp2.70006