In vitro and in vivo preclinical pharmacokinetic characterization of aficamten, a small molecule cardiac myosin inhibitor.

IF 1.3 4区 医学 Q4 PHARMACOLOGY & PHARMACY
Xenobiotica Pub Date : 2024-09-01 Epub Date: 2024-08-09 DOI:10.1080/00498254.2024.2389407
Rajaa Sukhun, Peadar Cremin, Donghong Xu, Jeanelle Zamora, Jennifer Cheung, Luke Ashcraft, Mark P Grillo, Bradley P Morgan
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引用次数: 0

Abstract

Aficamten, a small molecule selective inhibitor of cardiac myosin, was characterised in preclinical in vitro and in vivo studies.Protein binding in human plasma was 10.4% unbound and ranged from 1.6% to 24.9% unbound across species. Blood-to-plasma ratios ranged from 0.69 to 1.14 across species. Aficamten hepatic clearance in human was predicted to be low from observed high metabolic stability in vitro in human liver microsomes. Aficamten demonstrated high permeability in Caco-2 cell monolayers.Aficamten in vivo clearance was low across species at 8.8, 2.1, 3.3, and 11 mL/min/kg in mouse, rat, dog, and monkey, respectively. The volume of distribution was low-to-high ranging from 0.53 in rat to 11 L/kg in dog. Oral bioavailability ranged from 41% in monkey to 98% in mouse.Aficamten was metabolised in vitro to eight metabolites with hydroxylated metabolites M1a and M1b predominating. CYP phenotyping indicated multiple CYPs (2C8, 2C9, 2D6, and 3A4) contributing to the metabolism of aficamten.Human clearance (1.1 mL/min/kg) and volume of distribution (6.5 L/kg) were predicted using 4-species allometry employing 'rule-of-exponents'. A predicted 69 hour half-life is consistent with observed half-life in human Phase-1.No CYP-based drug-drug interaction liability as a precipitant was predicted for aficamten.

小分子心肌肌球蛋白抑制剂 Aficamten 的体外和体内药代动力学临床前表征。
Aficamten是一种小分子心肌酶选择性抑制剂,临床前研究对其进行了表征。在人体血浆中,蛋白质结合率为10.4%,不同物种的结合率从1.6%到24.9%不等。不同物种的血浆比为 0.69 至 1.14。根据在人体肝脏微粒体中观察到的高代谢稳定性,推测 Aficamten 在人体内的肝清除率较低。Aficamten在Caco-2细胞单层中的渗透性较高。Aficamten在小鼠、大鼠、狗和猴子体内的清除率较低,分别为8.8、2.1、3.3和11 mL/min/kg。分布容积从低到高依次为大鼠的 0.53 升/千克到狗的 11 升/千克。阿非坎顿在体外代谢为八种代谢物,羟化代谢物 M1a 和 M1b 占主导地位。CYP表型分析表明,多种CYP(2C8、2C9、2D6和3A4)参与了阿非卡姆登的代谢。采用 "指数规则 "的4种异构测定法预测了阿非卡姆登的人体清除率(1.1 mL/min/kg)和分布容积(6.5 L/kg)。预测的69小时半衰期与观察到的人体1期半衰期一致。
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来源期刊
Xenobiotica
Xenobiotica 医学-毒理学
CiteScore
3.80
自引率
5.60%
发文量
96
审稿时长
2 months
期刊介绍: Xenobiotica covers seven main areas, including:General Xenobiochemistry, including in vitro studies concerned with the metabolism, disposition and excretion of drugs, and other xenobiotics, as well as the structure, function and regulation of associated enzymesClinical Pharmacokinetics and Metabolism, covering the pharmacokinetics and absorption, distribution, metabolism and excretion of drugs and other xenobiotics in manAnimal Pharmacokinetics and Metabolism, covering the pharmacokinetics, and absorption, distribution, metabolism and excretion of drugs and other xenobiotics in animalsPharmacogenetics, defined as the identification and functional characterisation of polymorphic genes that encode xenobiotic metabolising enzymes and transporters that may result in altered enzymatic, cellular and clinical responses to xenobioticsMolecular Toxicology, concerning the mechanisms of toxicity and the study of toxicology of xenobiotics at the molecular levelXenobiotic Transporters, concerned with all aspects of the carrier proteins involved in the movement of xenobiotics into and out of cells, and their impact on pharmacokinetic behaviour in animals and manTopics in Xenobiochemistry, in the form of reviews and commentaries are primarily intended to be a critical analysis of the issue, wherein the author offers opinions on the relevance of data or of a particular experimental approach or methodology
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