Clinical Pharmacology Modelling and Simulation, GlaxoSmithKline, 1-2 Iron Bridge Road, Stockley Park West, Uxbridge, Middlesex, UB11 1BT, UK.
Eur J Clin Pharmacol. 2013 Jun;69(6):1261-7. doi: 10.1007/s00228-012-1469-1. Epub 2013 Jan 17.
The objective of this work was to describe the losmapimod concentration-QT relationship using meta-analysis of data from clinical trials with healthy volunteers and to evaluate the covariates that have significant impact on the QT prolongation.
Losmapimod plasma concentration and QT interval data were collected from six early clinical studies with healthy volunteers. The electrocardiograms (ECGs) were collected at baseline and at a number of post-dose time points (losmapimod or placebo). The population pharmacokinetic/pharmacodynamic (PK/PD) modelling approach was applied to investigate the relationship between losmapimod concentration and QT prolongation.
The dataset for analysis comprised 190 healthy adults who took at least one dose of losmapimod or placebo. Of the 2,494 QT observations collected, 1,532 observations had matched QT and losmapimod plasma concentration data. Population PK/PD analyses indicated that the model with the individual heart rate correction factor (α) fitted the data better than those using fixed α (0.33 for Fridericia's correction or 0.5 for Bazett's correction) and that there was no relationship between losmapimod concentration and QT interval. Female volunteers had about a 3 % higher QT interval at baseline than the male volunteers. No other covariates had a significant effect on the QT interval.
It is appropriate to apply population PK/PD analysis to investigate the effect of drug concentration on QT prolongation. Our meta-analysis of healthy volunteer data indicated no relationship between systemic losmapimod concentration and QT interval in healthy volunteers.
本研究旨在通过对健康志愿者临床试验数据的荟萃分析，描述洛马司培明的浓度- QT 关系，并评估对 QT 延长有显著影响的协变量。
从六项健康志愿者早期临床试验中收集洛马司培明的血浆浓度和 QT 间期数据。在基线和多个给药后时间点（洛马司培明或安慰剂）采集心电图（ECG）。应用群体药代动力学/药效学（PK/PD）模型方法来研究洛马司培明浓度与 QT 延长之间的关系。
用于分析的数据集包括 190 名至少服用过一次洛马司培明或安慰剂的健康成年人。在收集的 2494 次 QT 观察中，有 1532 次观察具有匹配的 QT 和洛马司培明血浆浓度数据。群体 PK/PD 分析表明，个体心率校正因子（α）的模型比使用固定α（Fridericia 校正为 0.33 或 Bazett 校正为 0.5）的模型更能拟合数据，并且洛马司培明浓度与 QT 间期之间没有关系。女性志愿者的基线 QT 间期比男性志愿者高约 3%。其他协变量对 QT 间期无显著影响。
应用群体 PK/PD 分析来研究药物浓度对 QT 延长的影响是恰当的。我们对健康志愿者数据的荟萃分析表明，健康志愿者中系统洛马司培明浓度与 QT 间期之间没有关系。
