注射用伏立康唑在中国健康受试者中单次和多次静脉给药后的耐受性和药代动力学研究

Tolerability and pharmacokinetics of voriconazole for injection after single and multiple intravenous administration in healthy Chinese volunteers

目的评价国产注射用伏立康唑在单次和多次静脉给药后的耐受性、安全性及药代动力学特征,并探讨细胞色素P4502C19(CYP2C19)基因多态性对伏立康唑药代动力学的影响。方法用单次和多次给药、随机、单盲研究设计。单次给药研究分为低、中、高3个剂量组(2、4和6 mg·kg^(-1)伏立康唑)。低、中剂量组各入组14例健康受试者,给药1次;高剂量组入组24例健康受试者,用交叉设计,两周期给药,每次静脉滴注2 h。多次给药组入组14例健康受试者,连续给药7 d,第1天给予6 mg·kg^(-1)伏立康唑,q12 h,第2~6天改为4 mg·kg^(-1),q12 h,第7天给予4 mg·kg^(-1),给药1次。用HPLC-MS/MS法检测伏立康唑的血浆药物浓度,用非房室模型计算药代动力学参数,用Power model方法对给药剂量与药物血浆暴露量的线性分析进行评价,并检测各受试者的CYP2C19基因多态性。结果单次给药研究高剂量组(6 mg·kg^(-1))受试制剂和参比制剂伏立康唑的药代动力学参数C_(max)、AUC_(0-t)和AUC_(0-∞)几何均值比值及其90%置信区间(CI)分别为102.18%(96.64%~108.04%)、100.21%(96.38%~104.18%)和100.97%(96.71%~105.43%),其几何均值比的90%CI均落在80.00%~125.00%。在2~6 mg·kg^(-1)内单次静脉滴注两制剂,其AUC_(0-t)和AUC_(0-∞)斜率β的90%置信区间未在判定区间,尚不能判断两制剂给药剂量与药物血浆暴露量为线性关系。多次给药研究中,受试制剂和参比制剂Css_max分别为(7883.43±1995.77)和(7716.50±2511.83)ng·mL^(-1),AUCss分别为(6.70±2.55)×10^(4)和(6.74±2.35)×10^(4)ng·mL^(-1)·h,CLss分别为(4000.58±2112.64)和(4062.52±1341.82)mL·h^(-1),两制剂暴露量相当,稳态清除率相近。各剂量组中CYP2C19慢代谢基因型受试者伏立康唑的暴露量依次高于中等代谢基因型受试者、快代谢基因型受试者。在安全性方面,总不良事件发生率为25.76%(17例),其中受试制剂8例和参比制剂9例。结论在原研注射用伏立康唑临床用量范围内中国健康受试者单次和多次静脉滴注国产注射用伏立康唑时安全性、耐受性良好,且药代动力学具有相似性,其代谢与CYP2C19基因多态性具有相关性。

Objective To evaluate the tolerability,safety and pharmacokinetic characteristics of domestic voriconazole for injection after single and multiple intravenous administration,and explore the effect of cytochrome P450,family 2,subfamily C,polypeptide 19(CYP2C19)gene polymorphism on the pharmacokinetics of voriconazole.Methods Single-and multiple-dose,randomized,single-blind study designs were used,and the single-dose study was divided into low-dose,medium-dose and high-dose group(2,4,6mg·kg^(-1)voriconazole),fourteen healthy volunteers were enrolled in the low-dose and medium-dose groups,and administered once.Twenty-four healthy volunteers were enrolled in the high-dose group,with a crossover design,two-cycle administration,and a constant-speed intravenous infusion for two hours each time by an intravenous infusion pump.Fourteen healthy volunteers were enrolled in the multiple-dose group for 7 consecutive days.The dosage on the first day was 6 mg·kg^(-1)q12 h,and the dosage on the second to sixth days was 4 mg·kg^(-1)q12 h,and the seventh day was 4 mg·kg^(-1),administered once.HPLC-MS/MS was used to detect the plasma drug concentration of voriconazole after administration,non-compartmental model was used to calculate the pharmacokinetic parameters of each subject.The power model method was used to evaluate the linear analysis of dose and drug plasma exposure,and detect the CYP2C19 gene polymorphism of each volunteers.Results The pharmacokinetic parameters C_(max),AUC_(0-t)and AUC_(0-∞)geometric mean ratio and 90%confidence interval(CI)of the test preparation and control preparation voriconazole in the high-dose group(6 mg·kg^(-1))of the single-dose study were 102.18%(96.64%-108.04%),100.21%(96.38%-104.18%)and 100.97%(96.71%-105.43%).The 90%CIs of the geometric mean ratios were all between 80.00%and 125.00%.In the dose range of 2-6 mg·kg^(-1),the 90%confidence interval of AUC_(0-t)and AUC_(0-∞)slopesβis not within the judgment interval.So a single intravenous drip of the two preparations cannot be judged to be a linear relationship between the doses and the drug plasma exposure.In multiple-dose studies,the C_(ss_max)of test and control preparation were(7883.43±1995.77)and(7716.50±2511.83)ng·mL^(-1),the AUC_(ss)were(6.70±2.55)×10^(4)and(6.74±2.35)×10^(4)ng·mL^(-1)·h,the CL_(ss)were(4000.58±2112.64)and(4062.52±1341.82)m L·h^(-1).The exposures of the two formulations were comparable,and the steady-state clearance was similar.The exposure of voriconazole in subjects with CYP2C19 slow metabolism genotype was higher than that in subjects with moderate metabolism genotype and fast metabolism genotype in each dose group.In terms of safety,the total incidence of adverse events was 25.76%(17 cases),test preparation was 8 cases and control preparation 9 cases.There were no new adverse reactions other than those reported in the instructions and no serious adverse reactions occurred.Conclusion Domestic voriconazole for injection is safe and well tolerated when given by single and multiple intravenous infusions to Chinese healthy volunteers within the clinical dosage range of the original research voriconazole for injection,and the pharmacokinetics are similar.Its metabolism is correlated with CYP2C19 gene polymorphism.(4000.58±2112.64)and(4062.52±1341.82)mL·h^(-1).The exposures of the two formulations were comparable,and the steady-state clearance was similar.The exposure of voriconazole in subjects with CYP2C19 slow metabolism genotype was higher than that in subjects with moderate metabolism genotype and fast metabolism genotype in each dose group.In terms of safety,the total incidence of adverse events was 25.76%(17 cases),test preparation was 8 cases and control preparation 9 cases.There were no new adverse reactions other than those reported in the instructions and no serious adverse reactions occurred.Conclusion Domestic voriconazole for injection is safe and well tolerated when given by single and multiple intravenous infusions to Chinese healthy volunteers within the clinical dosage range of the original research voriconazole for injection,and the pharmacokinetics are similar.Its metabolism is correlated with CYP2C19 gene polymorphism.