Pharmacokinetic interaction between amprenavir and rifabutin or rifampin in healthy males
Pharmacokinetic interaction between amprenavir and rifabutin or rifampin in healthy males
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DOI：
10.1128/aac.45.2.502-508.2001
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发表时间：
2001-02-01
影响因子：
4.9
通讯作者：
Stein, DS
中科院分区：
文献类型：
--
作者：
Polk, RE;Brophy, DF;Stein, DS
本研究的目的是确定氨丙那韦与利福平或利福平是否存在药代动力学相互作用，并确定这些药物对红霉素呼气试验(ERMBT)的影响。24名健康的男性受试者被随机分为两组。所有受试者服用氨丙那韦(1,200 mg，每天两次)，连续4天，然后是7天的冲洗期，然后是利福平(300 mg，每天一次[qd])(队列1)或利福平(600 mg，qd)(队列2)，持续14天。第1组服用氨丙那韦和利福平，疗程10天，第2组服用氨丙那韦和利福平，疗程4天。用高效液相色谱法测定血浆和尿样中氨丙那韦、利福平和利福平及其25-O-脱乙酰代谢物的浓度。利福布汀对氨丙那韦的药代动力学无显著影响。氨丙那韦使利福布汀的稳态曲线下面积(AUC(Ss))增加2.93倍，25-O-去乙酰利福布汀的AUC(Ss)增加13.3倍。利福平使氨丙那韦的AUC(Ss)降低82%，但对利福平的药代动力学无影响。Amprenavir将ERMBT结果降低了83%。利福平和利福平治疗2周后ERMBT分别提高187%和156%。氨丙那韦+利福平耐受性良好。氨丙那韦联合利福布汀耐受性差，11名受试者中有5名停止治疗。利福平显著增加氨丙那韦的代谢清除率，联合给药是禁忌的。氨丙那韦显著降低利福布汀和25-O-去乙酰利福布汀的清除量，且联合用药耐受性差。氨丙那韦对ERMBT有抑制作用，利福平和利福平对ERMBT的诱导作用相同。
The objective of this study was to determine if there is a pharmacokinetic interaction when amprenavir is given with rifabutin or rifampin and to determine the effects of these drugs on the erythromycin breath test (ERMBT). Twenty-four healthy male subjects were randomized to one of two cohorts. All subjects received amprenavir (1,200 mg twice a day) for 4 days, followed by a 7-days washout period, followed by either rifabutin (300 mg once a day [QD]) (cohort 1) or rifampin (600 mg QD) (cohort 2) for 14 days. Cohort 1 then received amprenavir plus rifabutin for 10 days, and cohort 2 received amprenavir plus rifampin for 4 days. Serial plasma and urine samples for measurement of amprenavir, rifabutin, and rifampin and their 25-O-desacetyl metabolites, were measured by high-performance liquid chromatography. Rifabutin did not significantly affect amprenavir's pharmacokinetics. Amprenavir significantly increased the area under the curve at steady state (AUC(ss)) of rifabutin by 2.93-fold and the AUC(ss) of 25-O-desacetylrifabutin by 13.3-fold. Rifampin significantly decreased the AUC(ss) of amprenavir by 82%, but amprenavir had no effect on rifampin pharmacokinetics. Amprenavir decreased the results of the ERMBT by 83%. The results of the ERMBT after 2 weeks of rifabutin and rifampin therapy were increased 187 and 156% respectively. Amprenavir plus rifampin was well tolerated. Amprenavir plus rifabutin was poorly tolerated, and 5 of 11 subjects discontinued therapy. Rifampin markedly increases the metabolic clearance of amprenavir, and coadministration is contraindicated. Amprenavir significantly decreases clearance of rifabutin and 25-O-desacetylrifabutin, and the combination is poorly tolerated. Amprenavir inhibits the ERMBT, and rifampin and rifabutin are equipotent inducers of the ERMBT.