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Antimicrobial Agents and Chemotherapy, February 2001, p. 502-508, Vol. 45, No. 2
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.2.502-508.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Pharmacokinetic Interaction between Amprenavir and Rifabutin or Rifampin in Healthy Males

Ronald E. Polk,1,* Donald F. Brophy,1 Debra S. Israel,1,dagger Roberto Patron,1 Brian M. Sadler,2 Gregory E. Chittick,2,Dagger William T. Symonds,2 Yu Lou,2 Debbie Kristoff,1 and D. S. Stein2

School of Pharmacy, Virginia Commonwealth University/Medical College of Virginia Campus, Richmond, Virginia,1 and Glaxo Wellcome, Inc., Research Triangle Park, North Carolina2

Received 31 March 2000/Returned for modification 26 August 2000/Accepted 28 October 2000

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 (AUCss) of rifabutin by 2.93-fold and the AUCss of 25-O-desacetylrifabutin by 13.3-fold. Rifampin significantly decreased the AUCss 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.

* Corresponding author. Mailing address: P.O. Box 980533, School of Pharmacy, Virginia Commonwealth University/Medical College of Virginia Campus, Richmond, VA 23298-0533. Phone: (804) 828-8317. Fax: (804) 828-8359. E-mail: rpolk{at}hsc.vcu.edu.

dagger Present address: Roche Pharmaceuticals, Austin, Tex.

Dagger Present address: Triangle Pharmaceuticals Inc., Durham, N.C.

Antimicrobial Agents and Chemotherapy, February 2001, p. 502-508, Vol. 45, No. 2
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.2.502-508.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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