title: Pharmacokinetic Interaction between amprenavir and rifabutin or rifampin in healthy males.
abstract: 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-day 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.
authors.affiliation: School of Pharmacy, Virginia Commonwealth University/Medical College of Virginia Campus, Richmond, Virginia 23298-0533, USA.
authors.forename: R E
authors.initials: RE
authors.lastname: Polk
authors.forename: D F
authors.initials: DF
authors.lastname: Brophy
authors.forename: D S
authors.initials: DS
authors.lastname: Israel
authors.forename: R
authors.initials: R
authors.lastname: Patron
authors.forename: B M
authors.initials: BM
authors.lastname: Sadler
authors.forename: G E
authors.initials: GE
authors.lastname: Chittick
authors.forename: W T
authors.initials: WT
authors.lastname: Symonds
authors.forename: Y
authors.initials: Y
authors.lastname: Lou
authors.forename: D
authors.initials: D
authors.lastname: Kristoff
authors.forename: D S
authors.initials: DS
authors.lastname: Stein
mesh_terms: D000293:Adolescent; D000328:Adult; D000900:Anti-Bacterial Agents; D000904:Antibiotics, Antitubercular / Q000493:pharmacokinetics*; D001711:Biotransformation; D001944:Breath Tests; D002219:Carbamates; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D003640:Dealkylation; D004347:Drug Interactions; D004917:Erythromycin; D005663:Furans; D006801:Humans; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D017828:Rifabutin / Q000493:pharmacokinetics*; D012293:Rifampin / Q000493:pharmacokinetics*; D013449:Sulfonamides / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine
chemical_list: D000900:Anti-Bacterial Agents; D000904:Antibiotics, Antitubercular; D002219:Carbamates; D065607:Cytochrome P-450 Enzyme Inhibitors; D005663:Furans; D013449:Sulfonamides; D017828:Rifabutin; C095108:amprenavir; D004917:Erythromycin; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; D012293:Rifampin