中国健康受试者单次负荷及维持剂量注射盐酸尼非卡兰的安全性和药效学研究

Pharmacodynamics and safety of single intravenous loading dose of nifekalant hydrochloride in healthy Chinese volunteers

目的评价中国健康受试者单次静脉注射低、中、高3个负荷剂量及维持剂量盐酸尼非卡兰的安全性及QT间期等药效学指标的变化。方法用随机双盲、安慰剂对照、剂量爬坡临床试验。低(0.15 mg·kg^(-1)+0.2 mg·kg^(-1)·h^(-1))、中(0.3 mg·kg^(-1)+0.4 mg·kg^(-1)·h^(-1))、高(0.5 mg·kg^(-1)+0.8 mg·kg^(-1)·h^(-1))3个剂量试验组,分别纳入14例、14例、10例受试者,每组分别有12例、12例、8例受试者给予试验药物,每组另外2例受试者给予安慰剂。根据体重计算给药量,药物溶于0.9%NaCl,负荷剂量为含盐酸尼非卡兰2 mg·mL^(-1)的液体,注射泵5 min匀速注射给药。维持剂量为含盐酸尼非卡兰1 mg·mL^(-1)的液体,静脉泵连续给药6 h。评价4组受试者给药前后QT间期、PR间期、QRS间期、RR间期、QTc间期指标的变化。结果低、中、高剂量试验组和安慰剂组受试者用药后血压无明显变化,低、中、高剂量试验组心率较基线略有下降,部分时间点心率的平均值低于60次/分,均在维持给药结束即刻恢复至正常。低、中、高剂量试验组受试者均于负荷给药5 min即出现QT间期延长,继续给予维持剂量尼非卡兰5 min达到第1个峰值,维持给药4 h达第2个峰值,QT间期分别为(443.78±17.79),(466.50±45.70),(492.75±38.06)ms,QTc间期的变化趋势同QT间期。低、中、高剂量试验组RR间期在负荷给药结束即刻出现延长,在维持给药4~6 h较基线明显下降,此后逐渐恢复。安慰剂组RR间期的变化趋势同试验组。低、中、高剂量试验组有4例受试者发生与研究药物相关的不良事件,表现为心电图异常(U波)、心电图异常(T波改变)、肝功能异常、皮疹,程度均为轻度,均未经处理自行恢复正常。本研究无严重不良事件。结论受试者单次静脉给予负荷及维持剂量盐酸尼非卡兰的安全性好,盐酸尼非卡兰抗心律失常的药效学指标QT间期延长具有剂量依赖性,维持给药6 h可以长时间保持QT间期延长。

Objective To evaluate the safety and the changes of pharmacodynamic parameters QT interval after single intravenous loading and maintaining dose of nifekalant hydrochloride at low,medium and high doses in healthy Chinese volunteers.Methods This is a randomized,double-blinded,placebo-controlled,dose-climbing clinical trial study.Low(0.15 mg·kg^(-1)+0.2 mg·kg^(-1)·h^(-1)),medium(0.3 mg·kg^(-1)+0.4 mg·kg^(-1)·h-1)and high(0.5 mg·kg^(-1)+0.8 mg·kg^(-1)·h-1)dose treatment groups were included in 14,14 and 10 subjects respectively,with 12,12 and 8 subjects receiving the e xperimental drug and 2 subjects in each group receiving placebo.The dosage was calculated according to body weight,and the drug was dissolved in 0.9%NaCl.The loading dose containing 2 mg·mL^(-1) nifekalant hydrochloride liquid was injected by injection pump at a constant speed in about 5 minutes.The maintaining dose of 1 mg·mL^(-1) nifekalant hydrochloride liquid was administered continuously by intravenous pump for 6 h.The changes of QT interval,PR interval,QRS interval,RR interval and QTc interval were evaluated.Results There were no significant changes in blood pressure in placebo group and treatment groups.Heart rate in low,medium and high dose treatment groups were decreased slightly from baseline.The mean heart rate at some time points was less than 60 beats·min^(-1) and returned to the baseline at the end of the maintaining dose.In low,medium and high dose treatment groups,QT interval prolonged immediately at 5 min of loading dose of Nifekalant,and reached the first peak at 5 min after the maintaining dose,and reached the second peak at 4 h of the maintaining dose were(443.78±17.79),(466.50±45.70)and(492.75±38.06)ms,respectively.The change trend of QTc interval was the same as QT interval.In low,medium and high dose groups,the RR interval prolonged immediately after loading dose,and decreased significantly from baseline at 4 to 6 h at maintaining dose,and then recovered to baseline gradually.The trend of RR interval in placebo group was the same as that in treatment group treatment.In low,medium and high dose treatment groups,there were 4 cases of adverse events related to the study drug,which showed abnormal electrocardiograph(ECG,U wave),abnormal ECG(t wave change),abnormal liver function and skin rash,were treated and returned to normal.There were no serious adverse events in this study.Conclusion The safety of single intravenous loading and maintaining dose of nifekalant hydrochloride was good,and the prolongation of QT interval was dose-dependent,long-term prolongation of the QT interval can be maintained by 6 hours of continuous administration.