合用CPY450酶抑制剂对伏立康唑安全性和药代动力学的影响的系统评价

摘要

Our objective was to systematically assess the effect of cytochrome P-450 (CYP450) inhibitors on pharmacokinetics and safety of voriconazole (VORI).Cochrane Library,PubMed,Embase,CNKI,CBM and WanFang databases and Clinicaltrials.gov were searched up to Jan.26th 2016.Two reviewers independently identified studies,extracted data and assessed quality of studies.Meta-analysis was performed with RevMan 5.3,and risk ratios (RRs) and mean differences (MDs) with 95％ confidence intervals (CIs) were calculated.A total of 12 studies were included:three crossover randomized controlled trials,three single-arm before-and-after studies and six cohort studies.Compared with non-combination group,the group of VORI plus omeprazole had a significantly higher occurrence of hepatic dysfunction (RR =4.11,95％ CI 1.12-15.08,P =0.03).However,neurologic dysfunction and visual disturbance were not significantly different.Pantoprazole,rabeprazole,cimetidine and contraceptive significantly increased the peak concentration (Cmax) and area under the curve (AUC) of VORI,while indinavir had no significant effect on pharmacokinetics of VORI.The effects of esomeprazole,erythromycin and azithromycin on pharmacokinetic parameters of VORI presented inconsistent results.Co-administration of VORI and CYP450 inhibitors was safe except for omeprazole.Although Cmax and A UC of VORI were increased while co-administered with a couple of CYP450 inhibitors,no significant effect on clinical outcomes was observed.%本研究旨在系统评价联用细胞色素P(CYP)450酶抑制剂对伏立康唑安全性和药代动力学的影响.截至2016年1月26日,计算机检索Cochrane图书馆、PubMed、Embase、CNKI、CBM、万方数据库和Clinicaltrials.gov,收集有关联用CYP450酶抑制剂对伏立康唑安全性与药代动力学参数影响的研究.两位作者独立检索文献,提取数据并评价文献质量.用RevMan 5.3软件对符合纳入标准的研究进行Meta分析,计算危险比(RRs)或均值差(MDs)及其95％置信区间.共纳入12篇研究:随机交叉研究3篇、单臂前后对照研究3篇、队列研究6篇.相比于伏立康唑单药组,伏立康唑联用奥美拉唑组患者肝功能损害发生率明显升高(RR=4.11,95％ CI 1.12-15.08,P=0.03);然而,两药合用后神经毒性和视觉障碍的发生率并无统计学差异.此外,泮托拉唑、雷贝拉唑、西咪替丁和口服避孕药可显著增加伏立康唑的血药峰浓度(Gmax)和药物-时间曲线下面积(A口UC),但是茚地那韦对伏立康唑的药动学无显著影响.艾司奥美拉唑、红霉素和阿奇霉素对伏立康唑的药动学参数影响结论不一致.除奥美拉唑外,伏立康唑与CYP450酶抑制剂联用较为安全.尽管部分CYP450酶抑制剂会增加伏立康唑的Cmax和AUC,但未观察到临床意义.