Pharmacokinetic interaction between amprenavir and rifabutin or rifampin in healthy males

The objective of this study was to determine if there is a pharmacokinetic interaction when amprenavir is given with rifabutin or rifampin and to dete rmine the effects of these drugs on the erythromycin breath test (ERMBT). T wenty-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 b y 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 t hen received amprenavir plus rifabutin for 10 days, and cohort 2 received a mprenavir plus rifampin for 4 days. Serial plasma and urine samples for mea surement of amprenavir, rifabutin, and rifampin and their 25-O-desacetyl me tabolites, were measured by high-performance liquid chromatography. Rifabut in did not significantly affect amprenavir's pharmacokinetics. Amprenavir s ignificantly increased the area under the curve at steady state (AUC(ss)) o f 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%, b ut amprenavir had no effect on rifampin pharmacokinetics. Amprenavir decrea sed 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 wa s poorly tolerated, and 5 of 11 subjects discontinued therapy. Rifampin mar kedly increases the metabolic clearance of amprenavir, and coadministration is contraindicated. Amprenavir significantly decreases clearance of rifabu tin and 25-O-desacetylrifabutin, and the combination is poorly tolerated. A mprenavir inhibits the ERMBT, and rifampin and rifabutin are equipotent ind ucers of the ERMBT.