Cassella James V, Spyker Daniel A, Yeung Paul P
Alexza Pharmaceuticals, Inc., Mountain View, CA and Teva Pharmaceuticals, Frazer, PA, USA.
Int J Clin Pharmacol Ther. 2015 Nov;53(11):963-71. doi: 10.5414/CP202457.
This randomized, double-blind, active- and placebo-controlled, crossover, thorough QT study assessed the effect of two inhaled loxapine doses on cardiac repolarization as measured by corrected QT (QTc) interval in healthy subjects (ClinicalTrials.gov NCT01854710).
Subjects received two doses of inhaled loxapine (10 mg) 2 hours apart+oral placebo, two doses of inhaled placebo+oral placebo, or two doses of inhaled placebo+oral moxifloxacin (400 mg; positive control), with ≥3 days washout between treatments. Two-sided 90% confidence intervals (CIs) were calculated around least-squares mean predose placebo-subtracted individually corrected QT durations (ΔΔTcIs) at 12 time points throughout 24 hours after dosing. A ΔΔTcI 95% upper CI exceeding 10 msec was the threshold indicating QTc prolongation (primary endpoint). Secondary endpoints included Fridericia- and Bazett-corrected QT duration and QTcI outliers. Pharmacokinetics and adverse events (AEs) were also assessed.
Of 60 subjects enrolled (mean age, 33.8 years; 52% male), 44 completed the study. Post loxapine dosing, no ΔΔTcI 95% upper CI exceeded 10 msec; the largest was 6.31 msec 5 minutes post dose 2. Methodology was validated by ΔΔTcI 95% lower CIs exceeding 5 msec at 9 of 12 time points after moxifloxacin dosing. Loxapine plasma concentrations increased rapidly (mean Cmax, 177 ng/mL; median tmax 2 minutes after dose 2, 2.03 hours after dose 1). There were no deaths, serious AEs, or AEs leading to discontinuation, and one severe AE.
Primary and secondary endpoints indicated two therapeutic doses of inhaled loxapine did not cause threshold QTc prolongation in this study.
这项随机、双盲、活性药物与安慰剂对照、交叉、全面QT研究评估了两种吸入用洛沙平剂量对健康受试者心脏复极的影响，通过校正QT（QTc）间期进行测量（ClinicalTrials.gov标识符：NCT01854710）。
受试者接受两剂吸入用洛沙平（10毫克），间隔2小时 + 口服安慰剂，两剂吸入用安慰剂 + 口服安慰剂，或两剂吸入用安慰剂 + 口服莫西沙星（400毫克；阳性对照），治疗之间洗脱期≥3天。在给药后24小时内的12个时间点，围绕最小二乘均值预给药安慰剂减去的个体校正QT持续时间（ΔΔTcI）计算双侧90%置信区间（CI）。ΔΔTcI的95%上界CI超过10毫秒是表明QTc延长的阈值（主要终点）。次要终点包括弗里德里西亚和巴泽特校正QT持续时间以及QTcI异常值。还评估了药代动力学和不良事件（AE）。
纳入的60名受试者（平均年龄33.8岁；52%为男性）中，44名完成了研究。洛沙平给药后，没有ΔΔTcI的95%上界CI超过10毫秒；最大为给药2后5分钟时的6.31毫秒。莫西沙星给药后12个时间点中的9个时间点，ΔΔTcI的95%下界CI超过5毫秒，验证了方法的有效性。洛沙平血浆浓度迅速升高（平均Cmax为177纳克/毫升；中位数tmax在给药2后为2分钟，给药1后为2.03小时）。没有死亡、严重AE或导致停药的AE，有1例严重AE。
主要和次要终点表明，在本研究中，两种治疗剂量的吸入用洛沙平未引起阈值QTc延长。
