咪唑安定
基于生理学的药代动力学模型
药代动力学
药理学
CYP3A4型
药物相互作用
曲线下面积
代谢物
CYP2C19型
医学
血浆浓度
药效学
不利影响
化学
细胞色素P450
内科学
新陈代谢
镇静
作者
Samira Merali,Caroline Sychterz,Vidya Perera,Lu Gaohua,Victoria Florea,Bindu Murthy
摘要
Abstract Mavacamten is a potential inducer of cytochrome P450 (CYP) 3A4 and could reduce the effectiveness of concomitant drugs that are metabolized by CYP3A4, such as midazolam. This study aimed to determine if repeat doses of mavacamten achieving clinically relevant exposures affected midazolam exposure. This was a single‐center, open‐label study in healthy participants. Participants received: on day 1, midazolam 5 mg; on days 2–3, mavacamten 25 mg; on days 4–16, mavacamten 15 mg; and on day 17, mavacamten 15 mg and midazolam 5 mg. Plasma concentrations of mavacamten, midazolam, and the midazolam metabolite 1′‐hydroxymidazolam were measured. A physiologically based pharmacokinetic (PBPK) model was used to simulate the effect of mavacamten‐mediated CYP3A4 induction on midazolam exposure by CYP2C19 phenotype. Thirteen adult participants were enrolled (46.2% were female; mean [SD] age: 34.0 [9.0] years). Compared with midazolam alone, midazolam coadministered with mavacamten decreased the maximum observed plasma concentration (C max ), area under the drug concentration‐time curve (AUC) from time zero to infinity (AUC 0‐inf ), and AUC from time zero to last measurable concentration (AUC 0‐last ) for midazolam by 7%, 13%, and 24%, respectively; for 1′‐hydroxymidazolam, AUC 0–inf and AUC 0–last increased by 20% and 11%, respectively. Ten participants experienced adverse events and the majority were mild in severity. The PBPK model predicted the clinical trial data well. The PBPK simulation assessed that the overall impact of mavacamten on midazolam C max and AUC was predicted to be weak regardless of CYP2C19 phenotype. At clinically relevant exposures, mavacamten had a negligible effect on midazolam exposure.
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