伊曲康唑与细胞色素P4503A(CYP3A)底物和调节CYP3A活性的药物临床相互作用研究

Clinical interaction of itraconazole with cytochrome P4503A(CYP3A)substrate and drugs regulating CYP3A activity

目的:分析伊曲康唑与其他三种与CYP3A4相互作用的药物之间的药物相互作用,以进一步丰富伊曲康唑的药物相互作用谱,为临床安全使用伊曲康唑提供数据基础。方法:40名健康受试者随机分为单独伊曲康唑给药组、伊曲康唑与左炔诺孕酮炔雌醇给药组、伊曲康唑与利福平给药组和伊曲康唑与利福布汀给药组进行PK分析和安全性分析。结果:与单独使用每种药物相比,伊曲康唑与伊曲康唑的共同给药改变了浓度-时间曲线下面积(AUC∞)和最大浓度(C max),如下所示:左炔诺孕酮炔雌醇不影响伊曲康唑的PK参数;利福平联用伊曲康唑相比伊曲康唑单用,暴露量下降约16%,终末半衰期消除下降约27%;利福布汀轻微影响伊曲康唑的PK参数。本研究中,没有死亡,常见不良事件为头痛,且导致研究中止的不良事件很少见。结论:伊曲康唑可以与左炔诺孕酮炔雌醇共同给药,不推荐伊曲康唑与强CYP3A诱导剂(如利福平)共同给药,也不推荐伊曲康唑与弱CYP3A诱导剂利福布汀同时给药。

Objective:To analyze the drug interactions between itraconazole and three other drugs that interact with CYP3A4,so as to further enrich the drug interaction spectrum of itraconazole and provide data basis for clinical safe use of itraconazole.Methods:40 healthy subjects were randomly divided into individual itraconazole group,itraconazole and levonorgestrel ethinyl estradiol group,itraconazole and rifampicin group,and itraconazole and rifobutine group for PK analysis and safety analysis.Results:Compared with each drug used alone,the area under the concentration time curve(AUC∞)and the maximum concentration(C max)of itraconazole and itraconazole were changed by co administration,as follows:Levonorgestrel ethinylestradiol did not affect the PK parameters of itraconazole;Compared with itraconazole alone,rifampicin combined with itraconazole reduced the exposure by about 16%,and the elimination of terminal half-life by about 27%;Rifabutin slightly affected the PK parameters of itraconazole.In this study,there was no death,the common adverse event was headache,and the adverse event leading to the discontinuation of the study was rare.Conclusion:Itraconazole can be administered with levonorgestrel and ethinylestradiol.Itraconazole is not recommended to be administered with a strong CYP3A inducer(such as rifampicin),nor is it recommended to be administered with a weak CYP3A inducer rifibutin.