Esperion Therapeutics, Inc., Ann Arbor, Michigan, USA.
Nonclinical Pharma Solutions, LLC, Dexter, Michigan, USA.
Clin Transl Sci. 2021 Nov;14(6):2487-2496. doi: 10.1111/cts.13116. Epub 2021 Aug 31.
Bempedoic acid is an inhibitor of adenosine triphosphate-citrate lyase approved for use in adults with hypercholesterolemia. Nonclinical studies assessed binding to the human ether-a-go-go-related gene (hERG) potassium channel in vitro and the effect of bempedoic acid on QT/QTc in cynomolgus monkeys. A randomized, double-blind, parallel-design clinical study assessed the effects of steady-state bempedoic acid at a supratherapeutic dose (240 mg/day, 33.3% higher the180 mg/day therapeutic dose), placebo, and moxifloxacin (400 mg) in healthy subjects. In vitro binding potency for bempedoic acid to the hERG potassium channel was weak, with half-maximal inhibition (IC ) estimated at greater than 1000 μM (>1670-fold the bempedoic acid 180 mg/day steady-state unbound maximum concentration). In monkeys, individual rate-corrected QT intervals showed no time- or dose-dependent changes up to 100 mg/kg of bempedoic acid. In human subjects, the upper 90% confidence interval (CI) for the difference in QTc interval, corrected using Fridericia's formula (QTcF), between bempedoic acid and placebo was less than 5 msec at all time points. Concentration-QTcF analysis showed that maximum bempedoic acid concentration at steady-state was attained at a median 2.1 h postdose, and the predicted mean change (90% CI) in QTcF at the observed mean bempedoic acid concentration 2 h postdose was -0.5 (-5.0, 4.0) msec. The lower bound of the moxifloxacin 90% CI exceeded 5 msec at prespecified time points, establishing study sensitivity. Steady-state bempedoic acid at a supratherapeutic dose of 240 mg was generally well-tolerated and not associated with QTc prolongation in healthy subjects.
贝匹地酸是一种三磷酸腺苷-柠檬酸裂解酶抑制剂，已被批准用于治疗高胆固醇血症的成年人。非临床研究评估了贝匹地酸在体外与人醚-a-go-go 相关基因（hERG）钾通道的结合情况，以及贝匹地酸对食蟹猴 QT/QTc 的影响。一项随机、双盲、平行设计的临床研究评估了在健康受试者中，贝匹地酸在治疗剂量（180mg/天）的基础上，以高治疗剂量（240mg/天，比 180mg/天高 33.3%）、安慰剂和莫西沙星（400mg）的稳态下的作用。体外实验表明，贝匹地酸对 hERG 钾通道的结合能力较弱，半数最大抑制（IC ）估计大于 1000μM（贝匹地酸 180mg/天稳态未结合最大浓度的 1670 倍以上）。在猴子中，个体速率校正 QT 间期在高达 100mg/kg 的贝匹地酸剂量下无时间或剂量依赖性变化。在人类受试者中，贝匹地酸与安慰剂相比，用 Fridericia 公式校正的 QTc 间期（QTcF）的差值，在所有时间点的 90%置信区间（CI）上限均小于 5ms。浓度-QTcF 分析表明，在稳态时，贝匹地酸的最大浓度在中位 2.1 小时达到，在观察到的平均贝匹地酸浓度 2 小时后，QTcF 的预测平均变化（90%CI）为-0.5（-5.0，4.0）ms。莫西沙星 90%CI 的下限在预设时间点超过 5ms，表明研究具有敏感性。在健康受试者中，以 240mg 的高治疗剂量给予贝匹地酸通常耐受性良好，与 QTc 延长无关。
