Tolbert Dwain, Gordon Judy, Harris Stuart, Walzer Mark, Bekersky Ihor, Reid Susan
Lundbeck LLC, Deerfield, Illinois.
Bay Pines VA Healthcare System, Bay Pines, Florida.
Clin Ther. 2017 Oct;39(10):2073-2086. doi: 10.1016/j.clinthera.2017.08.020. Epub 2017 Sep 27.
A thorough QT study was conducted to assess the proarrhythmic potential of clobazam and its active metabolite, N-desmethylclobazam (N-CLB).
In this Phase I, single-site, randomized, double-blind, double-dummy, parallel-group study, healthy participants were randomized to 1 of 4 treatment groups: clobazam 40 mg/d (maximum therapeutic dosage), clobazam 160 mg/d (supratherapeutic dosage), placebo, or moxifloxacin 400 mg (active control).
Of 280 enrolled participants (n = 70 per treatment arm), 250 (92%) completed the study; 194 were included in the pharmacokinetics population (clobazam 40 mg/d, n = 66; clobazam 160 mg/d, n = 62; and moxifloxacin, n = 66). Mean changes from baseline in QT interval placebo-corrected for heart rate using the Fridericia formula (primary end point), Bazett formula, and individual correction method (QTcF, QTcB, and QTcI, respectively) with clobazam 40 and 160 mg/d revealed no effect on QTc. No clinically relevant or treatment-related arrhythmias were observed, and there were no instances of second- or third-degree atrioventricular block. Given that clobazam is primarily demethylated to N-CLB by cytochrome P450 (CYP) enzyme, CYP3A4, the mean plasma time-concentration profile of clobazam was unchanged with the exclusion of CYP2C19 poor metabolizers. As N-CLB is metabolized by CYP2C19, the exclusion of CYP2C19 poor metabolizers resulted in slightly decreased mean plasma time-concentration profiles of N-CLB. Using a linear mixed-effects model, the effects of the clobazam and N-CLB C values on the placebo-corrected changes from baseline in QTcF, QTcI, and QTcB were near zero or slightly negative, and are not considered clinically important. The incidence of treatment-emergent adverse events was greatest in the clobazam groups (number of moderate AEs experienced by patients: PBO, 3/70; MOXI, 5/70; CLB 40 mg/d, 18/70; CLB 160 mg/d, 21/70; severe AEs: PBO, MOXI, & CLB 160 mg/d, 0; CLB 40 mg/d, 2/70); there were no serious AEs in any treatment group. A total of 10% of participants experienced benzodiazepine-withdrawal symptoms (16%, 23%, and 3% in the clobazam 40 and 160 mg/d groups and the moxifloxacin group, respectively).
The findings from this thorough QT study are consistent with existing clinical data and support the lack of proarrhythmic potential with clobazam.
开展一项全面的QT研究，以评估氯巴占及其活性代谢产物N-去甲基氯巴占（N-CLB）的促心律失常潜力。
在这项I期、单中心、随机、双盲、双模拟、平行组研究中，健康参与者被随机分配至4个治疗组之一：氯巴占40mg/天（最大治疗剂量）、氯巴占160mg/天（超治疗剂量）、安慰剂或莫西沙星400mg（活性对照）。
在280名入组参与者中（每个治疗组n = 70），250名（92%）完成了研究；194名被纳入药代动力学人群（氯巴占40mg/天，n = 66；氯巴占160mg/天，n = 62；莫西沙星，n = 66）。使用弗里德里西亚公式（主要终点）、巴泽特公式和个体校正方法（分别为QTcF、QTcB和QTcI）对心率进行安慰剂校正后，氯巴占40mg/天和160mg/天组的QT间期自基线的平均变化显示对QTc无影响。未观察到临床相关或与治疗相关的心律失常，也没有二度或三度房室传导阻滞的情况。鉴于氯巴占主要通过细胞色素P450（CYP）酶CYP3A4脱甲基生成N-CLB，排除CYP2C19慢代谢者后，氯巴占的平均血浆时间-浓度曲线未发生变化。由于N-CLB由CYP2C19代谢，排除CYP2C19慢代谢者导致N-CLB的平均血浆时间-浓度曲线略有下降。使用线性混合效应模型，氯巴占和N-CLB的C值对QTcF、QTcI和QTcB自基线的安慰剂校正变化的影响接近零或略为负值，不被认为具有临床重要性。治疗中出现的不良事件发生率在氯巴占组最高（患者经历的中度不良事件数量：安慰剂组，3/70；莫西沙星组，5/70；氯巴占40mg/天组，18/70；氯巴占160mg/天组，21/70；严重不良事件：安慰剂组、莫西沙星组和氯巴占160mg/天组，0；氯巴占40mg/天组，2/70）；任何治疗组均无严重不良事件。共有10%的参与者出现苯二氮䓬类戒断症状（氯巴占40mg/天组、160mg/天组和莫西沙星组分别为16%、23%和3%）。
这项全面的QT研究结果与现有临床数据一致，支持氯巴占缺乏促心律失常潜力的观点。
