注射用伏立康唑在中国健康受试者中的生物等效性研究

Bioequivalence study of voriconazole injection in Chinese healthy subjects

目的评价2种注射用伏立康唑在中国健康受试者体内的生物等效性及安全性,并探索辅料磺丁基-β-环糊精的安全性。方法本试验按照单中心、单剂量、随机、开放、两制剂、两周期、双交叉给药的试验设计。在空腹条件下,共纳入18例健康受试者,随机交叉单次静脉滴注伏立康唑受试制剂和参比制剂4 mg·kg^(-1),用高效液相色谱-串联质谱(HPLC-MS/MS)法测定血浆中伏立康唑和尿液中磺丁基-β-环糊精的浓度,用Phoenix WinNonlin 8.2软件计算血浆中伏立康唑的药代动力学(PK)参数,用SAS(9.4版本)软件计算尿液中磺丁基-β-环糊精的PK参数,并进行生物等效性评价。结果18例健康受试者空腹单次静脉滴注伏立康唑受试制剂和参比制剂后,血浆中伏立康唑主要PK参数:C_(max)分别为(2177.00±399.10)和(2265.00±378.70)ng·mL^(-1),AUC_(0-t)分别为(14612.07±8182.95)和(15144.69±7814.02)ng·h·mL^(-1),AUC_(0-∞)分别为(16217.48±10862.78)和(16863.18±10695.75)ng·h·mL^(-1),t_(max)分别为2.00和1.98 h。2种制剂的C_(max)、AUC_(0-t)和AUC_(0-∞)的几何均值比的90%置信区间均在等效范围80.00%~125.00%内。结论2种注射用伏立康唑在中国健康受试者空腹静脉滴注给药条件下具有生物等效性,且安全性良好。

Objective To evaluate the bioequivalence and safety of two voriconazole for injection in healthy Chinese subjects,and to explore the safety of the excipient sulfobutyl-β-cyclodextrin.Methods A single-center,single-dose,randomized,open-label,two-preparation,two-period,double-crossover trial design.A total of 18 healthy subjects were enrolled and administrated with a single intravenous infusion of voriconazole test drug and reference drug at 4 mg·kg^(-1)under fasting conditions,with a sequence determined by randomization.The concentrations of voriconazole in plasma and sulfobutyl-β-cyclodextrin in urine were determined by high performance liquid chromatography-tandem mass spectrometry(HPLC-MS/MS).Phoenix WinNonlin 8.2 software was used to calculate pharmacokinetic parameters of voriconazole in plasma,and SAS(version 9.4)software was used to calculate pharmacokinetic parameters of sulfobutyl-β-cyclodextrin in urine and bioequivalence analysis.Results Major pharmacokinetic parameters of voriconazole in plasma after a single intravenous infusion of voriconazole test drug and reference drug in 18 healthy subjects in a fasted state were as follows:C_(max)were(2177.00±399.10)and(2265.00±378.70)ng·mL^(-1);AUC_(0-t)were(14612.07±8182.95)and(15144.69±7814.02)ng·h·mL^(-1);AUC_(0-∞)were(16217.48±10862.78)and(16863.18±10695.75)ng·h·mL^(-1);t_(max)were 2.00 and 1.98 h,respectively.The 90%confidence intervals of the geometric mean ratios of Cmax,AUC_(0-t)and AUC_(0-∞)for the two drugs were within the equivalence range of 80.00%to 125.00%.Conclusion The two voriconazole for injection preparations were bioequivalent and safe when administered by intravenous infusion under fasting conditions in healthy Chinese subjects.