Barbour April M, Magee Mindy, Shaddinger Bonnie, Arya Niki, Tombs Lee, Tao Wenli, Patel Bela R, Fossler Michael J, Glaser Ruchira
GlaxoSmithKline, King of Prussia, PA, USA.
J Clin Pharmacol. 2015 Jun;55(6):661-70. doi: 10.1002/jcph.465. Epub 2015 Feb 13.
A thorough QT study was conducted in healthy volunteers with losmapimod. Four treatment regimens were included: a therapeutic dose (7.5 mg BID for 5 days), a supratherapeutic dose (20 mg QD for 5 days), a positive control (400 mg moxifloxacin single dose on Day 5), and placebo for 5 days. Baseline and on treatment ECGs were measured on Day 1 (3 timepoints predose) and Day 5, respectively. The primary statistical analysis failed to demonstrate a lack of effect of losmapimod on the QT interval leading to a positive finding. However, simulations using the concentration-effect model established for QTcF vs. losmapimod concentration at concentrations 4× the maximum concentration of the therapeutic dose did not exceed the regulatory thresholds of concern of 5 milliseconds for the mean (4.57 milliseconds) and 10 milliseconds for the upper bound of the 90%CI (90%CI 2.88, 6.10). Modeling demonstrated that the discrepant results may have been due to a baseline shift after repeat dosing and baseline differences between the treatments. Considering the results of the concentration-effect modeling, previous losmapimod data, and the high false-positive rate associated with the ICH E14 statistical analysis, the statistical analysis was likely a false-positive.
在健康志愿者中使用洛沙匹莫德进行了一项全面的QT研究。研究包括四种治疗方案：治疗剂量（7.5毫克，每日两次，共5天）、超治疗剂量（20毫克，每日一次，共5天）、阳性对照（第5天单次服用400毫克莫西沙星）和安慰剂，持续5天。分别在第1天（给药前3个时间点）和第5天测量基线和治疗期间的心电图。初步统计分析未能证明洛沙匹莫德对QT间期无影响，从而得出阳性结果。然而，使用针对QTcF与洛沙匹莫德浓度建立的浓度效应模型进行模拟，在浓度为治疗剂量最大浓度4倍时，平均变化（4.57毫秒）未超过5毫秒的监管关注阈值，90%置信区间上限（90%CI 2.88, 6.10）未超过10毫秒。建模表明，结果差异可能是由于重复给药后基线偏移以及各治疗组之间的基线差异。考虑到浓度效应建模结果、之前的洛沙匹莫德数据以及与ICH E14统计分析相关的高假阳性率，该统计分析可能是假阳性。
