Abstract：
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.
摘要：
Mavacamten是心肌肌球蛋白的小分子调节剂，设计为口服给药，用于治疗肥厚型心肌病患者。当前的研究目标是评估mavacamten的临床前药代动力学，以预测人给药剂量，并建立对表征药物-药物相互作用潜力的临床药代动力学研究的潜在需求。Mavacamten不抑制CYP酶，但在相对于预期治疗浓度的高浓度下，在体外诱导CYP2B6和CYP3A4酶。Mavacamten在Caco-2细胞膜上显示出高渗透性和低外排转运。在人类肝细胞中，mavacamten不是药物转运蛋白OATP的底物，OCT和NTCP。Mavacamten被确定为具有最小的药物-药物相互作用风险。体外mavacamten代谢物谱包括I期和II期介导的代谢交叉物种。主要途径包括芳香羟基化(M1)，脂肪族羟基化(M2);N-脱烷基化(M6),和M1代谢物(M4)的葡糖醛酸化。反应表型显示CYPs2C19和3A4/3A5占优势。Mavacamten表现出低间隙,大量的分布，长的终末消除半衰期和优异的口服生物利用度跨物种。简单的四物种异速缩放导致预测的血浆清除，分布体积和半衰期为0.51mL/min/kg，9.5L/kg和9天，分别,在人类。
