Mehta Rashmi, Green Michelle, Patel Bela, Wagg Jonathan
Clinical Pharmacology Modeling Simulation, GSK, 5 Moore Drive, Research Triangle Park, NC, 27709, USA.
Quantitative Solutions, Menlo Park, CA, USA.
J Pharmacokinet Pharmacodyn. 2016 Apr;43(2):153-64. doi: 10.1007/s10928-015-9461-x. Epub 2016 Jan 6.
The long-acting muscarinic antagonist umeclidinium (UMEC) is approved as a once-daily monotherapy and in combination with the long-acting β2 agonist vilanterol (VI) for chronic obstructive pulmonary disease. The objective of this analysis was to assess the relationship between observed plasma UMEC and/or VI concentrations and QT interval corrected using Fridericia's correction (QTcF). 103 subjects were enrolled and 86 (83 %) completed the study. Subjects were randomized to 4 of 5 repeat-dose treatments (days 1-10: n = 77 subjects received placebo, n = 76 UMEC 500 µg, n = 78 UMEC/VI 125/25 µg, or n = 76 UMEC/VI 500/100 µg; day 10: n = 74 oral tablet moxifloxacin 400 mg [positive control]). The concentration-QTcF interval relationship was examined using nonlinear mixed-effects methods. For UMEC, predicted QTcF interval prolongation (at observed geometric mean of maximum plasma concentrations) was -2.38 ms (90 % prediction interval [PI] -3.82, -0.85) with UMEC 500 µg and -0.50 ms (90 % PI -0.80, -0.18) and -2.01 ms (90 % PI -3.22, -0.72) with UMEC/VI 125/25 µg and 500/100 µg, respectively. For VI, estimates were 5.89 ms (90 % PI 4.89, 6.91) and 7.23 ms (90 % PI 5.88, 8.55) with UMEC/VI 125/25 µg and 500/100 µg, respectively. Combined additive mean effects were estimated for UMEC/VI 125/25 µg (5.39 ms [90 % PI 4.40, 6.47]) and 500/100 µg (5.22 ms [90 % PI 3.72, 6.80]). The model-predicted decrease with UMEC and increase with UMEC/VI combination in QTcF interval suggest that the QT effect is likely attributable to VI. These model-predicted results support those of previously-published traditional statistical analyses.
长效毒蕈碱拮抗剂乌美溴铵（UMEC）已被批准作为每日一次的单一疗法，以及与长效β2激动剂维兰特罗（VI）联合用于慢性阻塞性肺疾病。本分析的目的是评估观察到的血浆UMEC和/或VI浓度与使用弗里德里西亚校正法校正的QT间期（QTcF）之间的关系。共纳入103名受试者，86名（83%）完成了研究。受试者被随机分配至5种重复给药治疗方案中的4种（第1 - 10天：77名受试者接受安慰剂，76名接受500μg乌美溴铵，78名接受125/25μg乌美溴铵/维兰特罗，或76名接受500/100μg乌美溴铵/维兰特罗；第10天：74名口服400mg莫西沙星片[阳性对照]）。使用非线性混合效应方法检查浓度 - QTcF间期关系。对于乌美溴铵，在500μg乌美溴铵组中，预测的QTcF间期延长（在观察到的最大血浆浓度几何均值时）为 - 2.38ms（90%预测区间[PI] - 3.82， - 0.85），在125/25μg乌美溴铵/维兰特罗组和500/100μg乌美溴铵/维兰特罗组中分别为 - 0.50ms（90%PI - 0.80， - 0.18）和 - 2.01ms（90%PI - 3.22， - 0.72）。对于维兰特罗，在125/25μg乌美溴铵/维兰特罗组和500/100μg乌美溴铵/维兰特罗组中的估计值分别为5.89ms（90%PI 4.89，6.91）和7.23ms（90%PI 5.88，8.55）。对125/25μg乌美溴铵/维兰特罗组（5.39ms[90%PI 4.40，6.47]）和500/100μg乌美溴铵/维兰特罗组（5.22ms[90%PI 3.72，6.80]）估计了联合相加平均效应。模型预测的QTcF间期随乌美溴铵降低以及随乌美溴铵/维兰特罗组合升高表明，QT效应可能归因于维兰特罗。这些模型预测结果支持先前发表的传统统计分析结果。
