Hepatotoxicity and gastrointestinal intolerance when healthy volunteers taking rifampin add twice-daily atazanavir and ritonavir.
Hepatotoxicity and gastrointestinal intolerance when healthy volunteers taking rifampin add twice-daily atazanavir and ritonavir.
复制标题
DOI：
10.1097/qai.0b013e318189a7df
复制
发表时间：
2009-03-01
期刊：
影响因子：
--
通讯作者：
A5213 StudyTeam
中科院分区：
文献类型：
--
作者：
Haas DW;Koletar SL;Laughlin L;Kendall MA;Suckow C;Gerber JG;Zolopa AR;Bertz R;Child MJ;Hosey L;Alston-Smith B;Acosta EP;A5213 StudyTeam
利福平是抗结核治疗的基石，但利福平诱导肝细胞色素 P450 (CYP) 3A 显着降低 HIV 蛋白酶抑制剂血浆浓度。这项 I 期、开放标签、单臂研究旨在评估 14 名可评估的 HIV 血清阴性志愿者中阿扎那韦、利托那韦和利福平的药代动力学相互作用和安全性。该研究包括三个连续的研究药物给药周期，在每个周期的最后一天进行血浆采样以进行药代动力学分析。在第 1 阶段，参与者每 24 小时接受利福平 600 毫克，持续 8 天。在第 2 阶段，参与者继续每 24 小时服用利福平 600 毫克，并每 12 小时添加阿扎那韦 300 毫克和利托那韦 100 毫克，持续至少 11 天。在第 3 阶段，阿扎那韦的剂量将增加至每 12 小时 400 毫克。添加阿扎那韦和利托那韦后，前三名受试者出现呕吐和转氨酶升高，导致研究药物停止。该研究因此终止。如果利福平先于蛋白酶抑制剂给药，则利福平与 HIV 蛋白酶抑制剂联合给药可能不是可行的治疗选择。未来探索 HIV 蛋白酶抑制剂与利福平联合使用的研究必须仔细考虑药物的起始顺序。
Rifampin is the cornerstone of antituberculosis therapy, but induction of hepatic cytochrome P450 (CYP) 3A by rifampin markedly lowers HIV protease inhibitor plasma concentrations. This phase I, open-label, one-arm study was designed to assess pharmacokinetic interactions and safety of atazanavir, ritonavir, and rifampin among 14 evaluable HIV-seronegative volunteers. The study included three sequential periods of study drug dosing, with plasma sampling for pharmacokinetic analyses to occur on the last day of each period. During period 1, participants received rifampin 600 mg every 24 hours for 8 days. During period 2, participants continued rifampin 600 mg every 24 hours, and added atazanavir 300 mg and ritonavir 100 mg every 12 hours, to continue for at least 11 days. During period 3, atazanavir was to be increased to 400 mg every 12 hours. Upon adding atazanavir and ritonavir, the first three subjects developed vomiting and transaminase elevations resulting in study drug discontinuation. The study was therefore terminated. Co-administration of rifampin with HIV protease inhibitors may not be a viable treatment option if rifampin administration precedes protease inhibitor initiation. Future studies which explore concomitant HIV protease inhibitors with rifampin must carefully consider the sequence in which drugs are initiated.