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Antimicrobial Agents and Chemotherapy, September 2007, p. 3104-3110, Vol. 51, No. 9
0066-4804/07/$08.00+0     doi:10.1128/AAC.00341-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Effect of Concomitantly Administered Rifampin on the Pharmacokinetics and Safety of Atazanavir Administered Twice Daily ^,

Edward P. Acosta,¹ Michelle A. Kendall,² John G. Gerber,³ Beverly Alston-Smith,⁴ Susan L. Koletar,⁵ Andrew R. Zolopa,⁶ Sangeeta Agarwala,⁷ Michael Child,⁷ Richard Bertz,⁷ Lara Hosey,⁸ and David W. Haas^9*

University of Alabama at Birmingham, Birmingham, Alabama,¹ Statistical and Data Analysis Center, Harvard School of Public Health, Boston, Massachusetts,² University of Colorado Health Sciences Center, Denver, Colorado,³ DAIDS, NIAID, NIH, Bethesda, Maryland,⁴ Ohio State University, Columbus, Ohio,⁵ Stanford University, Stanford, California,⁶ Bristol-Myers Squibb, Princeton, New Jersey,⁷ Social & Scientific Systems Inc., Silver Spring, Maryland,⁸ Vanderbilt University School of Medicine, Nashville, Tennessee⁹

Received 13 March 2007/ Returned for modification 9 June 2007/ Accepted 11 June 2007

The potent induction of hepatic cytochrome P450 3A isoforms by rifampin complicates therapy for coinfection with human immunodeficiency virus (HIV) and Mycobacterium tuberculosis. We performed an open-label, single-arm study to assess the safety and pharmacokinetic interactions of the HIV protease inhibitor atazanavir coadministered with rifampin. Ten healthy HIV-negative subjects completed pharmacokinetic sampling at steady state while receiving 300 mg atazanavir every 12 h without rifampin (period 1), 300 mg atazanavir every 12 h with 600 mg rifampin every 24 h (period 2), and 400 mg atazanavir every 12 h with 600 mg rifampin every 24 h (period 3). During period 1, the mean concentration of drug in serum at 12 h (C_{12 h}) was 811 ng/ml (range, 363 to 2,484 ng/ml) for atazanavir, similar to historic seronegative data for once-daily treatment with 300 mg atazanavir boosted with 100 mg ritonavir. During periods 2 and 3, the mean C_{12 h} values for atazanavir were 44 ng/ml (range, <25 to187 ng/ml) and 113 ng/ml (range, 39 to 260 ng/ml), respectively, well below historic seronegative data for once-daily treatment with 400 mg atazanavir without ritonavir. Although safe and generally well tolerated, 300 mg or 400 mg atazanavir administered every 12 h did not maintain adequate plasma exposure when coadministered with rifampin.

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* Corresponding author. Mailing address: Division of Infectious Diseases, Vanderbilt University School of Medicine, 345 24th Avenue North, Suite 105, Nashville, TN 37203. Phone: (615) 467-0154. Fax: (615) 467-0158. E-mail: david.w.haas{at}vanderbilt.edu

Published ahead of print on 18 June 2007.

This is ACTG study A5213.

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Antimicrobial Agents and Chemotherapy, September 2007, p. 3104-3110, Vol. 51, No. 9
0066-4804/07/$08.00+0     doi:10.1128/AAC.00341-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.