Pharmacokinetic interaction between rifampicin and the once-daily combination of saquinavir and low-dose ritonavir in HIV-infected patients with tuberculosis
Pharmacokinetic interaction between rifampicin and the once-daily combination of saquinavir and low-dose ritonavir in HIV-infected patients with tuberculosis
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DOI：
10.1093/jac/dkl552
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发表时间：
2007-04-01
影响因子：
5.2
通讯作者：
Pahissa, Albert
中科院分区：
文献类型：
--
作者：
Ribera, Esteban;Azuaje, Carlos;Pahissa, Albert
目的：评估利福平、异烟肼、沙奎那韦和利托那韦在HIV和结核病（TB）合并感染患者的血浆稳态药代动力学（PK），并探讨结核病药物与蛋白酶抑制剂（Pis）之间的潜在相互作用。方法：开放标签、单臂、序贯PK研究，纳入22例Hill感染合并结核患者。在前2个月，患者接受利福平、异烟肼和吡嗪酰胺治疗，伴用或不伴用乙胺丁醇（第一次PK研究，n = 22）。然后患者停用吡嗪酰胺和乙胺丁醇，开始每日一次抗逆转录病毒治疗（ART），使用二腺苷、拉米夫定、利托那韦（200 mg）和沙奎那韦（1600 mg）（第二次PK研究，n = 18）。患者在接受相同ART治疗9个月后停用所有结核药物（第三次PK研究，n = 15）。采用第一次和第二次PK研究中结核病药物参数的差异，以及第二次和第三次PK研究中Pi参数的差异来评估相互作用。结果：沙奎那韦和利托那韦对利福平和异烟肼的药代动力学无明显影响。利福平组和异烟肼组沙奎那韦中位AUC（0-24）、C-max和c -谷值分别显著降低39.5%、34.9%和48.7%。利托那韦的AUC（0-24）、C-max和c -谷分别比利福平和异烟肼降低42.5%、49.6%和64.3%。结论：沙奎那韦、利托那韦和利福平之间存在显著的相互作用，降低了沙奎那韦和利托那韦的中位血浆浓度。接受利福平治疗的患者应谨慎使用沙奎那韦。每日两次给药或每日一次给药的更高剂量沙奎那韦应进行测试以获得更合适的血浆水平。
Objectives: To assess plasma steady-state pharmacokinetics (PK) of rifampicin, isoniazid, saquinavir and ritonavir in HIV and tuberculosis (TB) co-infected patients, and investigate potential interactions between TB drugs and protease inhibitors (Pis). Methods: Open-label, single-arm, sequential PK study including 22 patients with Hill infection and TB. During the first 2 months, patients received rifampicin, isoniazid and pyrazinamide, with or without ethambutol (first PK study, n = 22). Then patients stopped pyrazinamide and ethambutol and started once-daily antiretroviral therapy (ART) with didanosine, lamivudine, ritonavir (200 mg) and saquinavir (1600 mg) (second PK study, n = 18). Patients stopped all TB drugs after 9 months continuing the same ART (third PK study, n = 15). Differences between TB drug parameters in the first and second PK studies, and between Pi parameters in the second and third PK studies were used to assess interactions. Results: Rifampicin and isoniazid pharmacokinetics did not change substantially with saquinavir and ritonavir. A significant 39.5%, 34.9% and 48.7% reduction in median saquinavir AUC(0-24), C-max, and C-trough, respectively, was seen with rifampicin and isoniazid. Ritonavir AUC(0-24), C-max and C-trough decreased 42.5%, 49.6% and 64.3%, respectively, with rifampicin and isoniazid. Conclusions: There was a significant interaction between saquinavir, ritonavir and rifampicin, with reduction in median plasma concentrations of saquinavir and ritonavir. Saquinavir should be given with caution in patients receiving rifampicin. Twice-daily dosing or higher saquinavir doses in once-daily administration should be tested to obtain more appropriate plasma levels.