Infectious Diseases Medicines Discovery and Development, GlaxoSmithKline, Research Triangle Park, North Carolina, USA.
Pharmacotherapy. 2013 Jul;33(7):701-9. doi: 10.1002/phar.1261. Epub 2013 Apr 3.
To assess the effect of a therapeutic and supratherapeutic intravenous dose of the neuraminidase inhibitor zanamivir on QT and rate-corrected QT intervals.
Randomized, placebo-controlled, single-dose, four-period, balanced crossover study.
Clinical research unit.
Forty healthy adults were randomized to receive intravenous zanamivir at two dose levels, oral moxifloxacin, and placebo; 38 subjects completed all four study treatments.
Subjects were randomized to receive a single intravenous dose of zanamivir 600 mg (therapeutic dose) with oral moxifloxacin placebo, a single intravenous dose of zanamivir 1200 mg (supratherapeutic dose) with oral moxifloxacin placebo, oral moxifloxacin 400 mg (positive control) with intravenous zanamivir placebo, or intravenous zanamivir placebo with oral moxifloxacin placebo. Subjects crossed over to all other treatments, with each treatment separated by a 7-day washout period.
Zanamivir pharmacokinetics were dose proportional; the pharmacokinetic exposure from zanamivir 1200 mg was 2 times higher than that from 600 mg, the maximum dose under clinical evaluation. For both 600-mg and 1200-mg doses of intravenous zanamivir, the upper limit of the 90% confidence interval (CI) for the placebo-adjusted mean change from baseline of the QT interval corrected for heart rate using Fridericia's formula (ΔΔQTcF) was less than 10 msec at all time points. The sensitivity of the study to detect modest increases in QT interval was established with the positive control, moxifloxacin. The maximum ΔΔQTcF value for zanamivir 1200 mg was 1.73 msec (90% CI -0.40 to 3.87 msec), which was observed within 30 minutes after dosing, and 11.21 msec (90% CI 8.81-13.60) for moxifloxacin, observed at 4 hours after dosing. No relationship was observed between zanamivir serum concentration and ΔΔQTcF. Zanamivir was generally well tolerated, with very few adverse events; none were serious or severe.
Intravenous zanamivir does not affect cardiac repolarization. Accordingly, treatment with intravenous zanamivir does not require additional cardiac monitoring beyond the standard of care.
评估治疗剂量和超治疗剂量的神经氨酸酶抑制剂扎那米韦对 QT 和心率校正 QT 间期的影响。
随机、安慰剂对照、单剂量、四期、平衡交叉研究。
临床研究单位。
40 名健康成年人被随机分为两组，分别接受静脉扎那米韦两种剂量水平、口服莫西沙星和安慰剂；38 名受试者完成了所有 4 种研究治疗。
受试者随机接受单次静脉扎那米韦 600mg（治疗剂量）联合口服莫西沙星安慰剂、单次静脉扎那米韦 1200mg（超治疗剂量）联合口服莫西沙星安慰剂、口服莫西沙星 400mg（阳性对照）联合静脉扎那米韦安慰剂或静脉扎那米韦安慰剂联合口服莫西沙星安慰剂。受试者交叉接受所有其他治疗，每种治疗之间间隔 7 天洗脱期。
扎那米韦的药代动力学呈剂量依赖性；扎那米韦 1200mg 的药代动力学暴露量是 600mg 的 2 倍，这是临床评估下的最大剂量。对于静脉扎那米韦的 600mg 和 1200mg 剂量，用 Fridericia 公式校正心率后的 QT 间期（QTcF）的安慰剂调整平均变化的上限 90%置信区间（CI）在所有时间点均小于 10ms。阳性对照药物莫西沙星的研究敏感性可检测 QT 间期的适度增加。扎那米韦 1200mg 的最大ΔΔQTcF 值为 1.73ms（90%CI -0.40 至 3.87ms），在给药后 30 分钟内观察到，莫西沙星的最大ΔΔQTcF 值为 11.21ms（90%CI 8.81-13.60），在给药后 4 小时观察到。扎那米韦血清浓度与ΔΔQTcF 之间未观察到相关性。静脉扎那米韦通常耐受性良好，仅有极少数不良事件；均非严重或重度不良事件。
静脉扎那米韦不会影响心脏复极。因此，静脉扎那米韦治疗不需要超出常规护理的额外心脏监测。
