Vlasakakis Georgios, Alvarez Yolanda, Hart Timothy, Ho Yu Liu, Ellis Catherine
GSK, Collegeville, PA, USA.
GSK, London, UK.
Clin Pharmacol Drug Dev. 2025 Apr;14(4):333-342. doi: 10.1002/cpdd.1509. Epub 2025 Jan 23.
A randomized, partially blinded, placebo-controlled, crossover study in 48 healthy adults assessed the effect of momelotinib on the heart rate-corrected QT interval (QTc) using the Fridericia formula (QTcF). QTc was evaluated for momelotinib 200 mg (therapeutic dose), momelotinib 800 mg (supratherapeutic dose), moxifloxacin 400 mg (positive control), and placebo. Pharmacokinetic profiles of momelotinib and its active metabolite M21 were evaluated. Momelotinib did not prolong QTcF, as the upper bounds of the 2-sided 90% confidence intervals (CIs) for the mean difference between doses of momelotinib and placebo were <10 milliseconds at all time points. The lower limit of the 2-sided 98% CI for the mean difference in QTcF between moxifloxacin versus placebo was >5 milliseconds at 2, 3, and 4 hours after dosing, demonstrating assay sensitivity. There was no positive relationship between momelotinib plasma concentrations and QTcF. Adverse events (AEs) were more frequent with the supratherapeutic dose of momelotinib, but none were considered severe. There were no deaths, serious AEs, or AEs leading to study discontinuation. Neither therapeutic nor supratherapeutic doses of momelotinib led to clinically significant effects on the QTc interval, supporting a negative finding for QTc prolongation from this thorough QT study.
一项针对48名健康成年人的随机、部分盲法、安慰剂对照、交叉研究，使用弗里德里西亚公式（QTcF）评估了莫美替尼对心率校正QT间期（QTc）的影响。对莫美替尼200毫克（治疗剂量）、莫美替尼800毫克（超治疗剂量）、莫西沙星400毫克（阳性对照）和安慰剂进行了QTc评估。评估了莫美替尼及其活性代谢物M21的药代动力学特征。莫美替尼未延长QTcF，因为在所有时间点，莫美替尼与安慰剂剂量之间平均差异的双侧90%置信区间（CI）上限均<10毫秒。给药后2、3和4小时，莫西沙星与安慰剂之间QTcF平均差异双侧98%CI的下限>5毫秒，表明检测具有敏感性。莫美替尼血浆浓度与QTcF之间无正相关关系。超治疗剂量的莫美替尼不良事件（AE）更频繁，但均不被认为严重。没有死亡、严重AE或导致研究中断的AE。治疗剂量和超治疗剂量的莫美替尼均未对QTc间期产生临床显著影响，支持了这项全面QT研究中QTc延长的阴性结果。
