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Antimicrobial Agents and Chemotherapy, May 2004, p. 1553-1560, Vol. 48, No. 5
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.5.1553-1560.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Pharmacokinetics of Adjusted-Dose Lopinavir-Ritonavir Combined with Rifampin in Healthy Volunteers

C. J. L. la Porte,1,2* E. P. H. Colbers,3 R. Bertz,4 D. S. Voncken,3 K. Wikstrom,4 M. J. Boeree,2,5 P. P. Koopmans,2,6 Y. A. Hekster,1,2 and D. M. Burger1,2

Department of Clinical Pharmacy,1 Department of General Medicine, University Medical Centre Nijmegen,6 Nijmegen University Centre for Infectious Diseases,2 Farma Research BV,3 University Lung Centre Dekkerswald, Nijmegen, The Netherlands,5 Department of Clinical Pharmacokinetics and Antiviral Global Development, Abbott Laboratories, Abbott Park, Illinois4

Received 8 October 2003/ Returned for modification 4 December 2003/ Accepted 3 February 2004

Coadministration of lopinavir-ritonavir, an antiretroviral protease inhibitor, at the standard dose (400/100 mg twice a day [BID]) with the antituberculous agent rifampin is contraindicated because of a significant pharmacokinetic interaction due to induction of cytochrome P450 3A by rifampin. In the present study, two adjusted-dose regimens of lopinavir-ritonavir were tested in combination with rifampin. Thirty-two healthy subjects participated in a randomized, two-arm, open-label, multiple-dose, within-subject controlled study. All subjects were treated with lopinavir-ritonavir at 400/100 mg BID from days 1 to 15. From days 16 to 24, the subjects in arm 1 received lopinavir-ritonavir at 800/200 mg BID in a dose titration, and the subjects in arm 2 received lopinavir-ritonavir at 400/400 mg BID in a dose titration. Rifampin was given at 600 mg once daily to all subjects from days 11 to 24. The multiple-dose pharmacokinetics of lopinavir, ritonavir, and rifampin were assessed. Twelve of 32 subjects withdrew from the study. For nine subjects lopinavir-ritonavir combined with rifampin resulted in liver enzyme level elevations. Pharmacokinetic data for 19 subjects were evaluable. Geometric mean ratios for the lopinavir minimum concentration in serum and the maximum concentration in serum (Cmax) on day 24 versus that on day 10 were 0.43 (90% confidence interval [CI], 0.19 to 0.96) and 1.02 (90% CI, 0.85 to 1.23), respectively, for arm 1 (n = 10) and 1.03 (90% CI, 0.68 to 1.56) and 0.93 (90% CI, 0.81 to 1.07), respectively, for arm 2 (n = 9). Ritonavir exposure increased from days 10 to 24 in both arms. The geometric mean Cmax of rifampin was 13.5 mg/liter (day 24) and was similar between the two arms. Adjusted-dose regimens of lopinavir-ritonavir in combination with therapeutic drug monitoring and monitoring of liver function may allow concomitant use of rifampin.

* Corresponding author. Mailing address: Department of Clinical Pharmacy, University Medical Centre Nijmegen, P.O. Box 9101, 533 KF, 6500 HB Nijmegen, The Netherlands. Phone: 31-24-3616405. Fax: 31-24-3540331. E-mail: C.laPorte{at}akf.umcn.nl.

Antimicrobial Agents and Chemotherapy, May 2004, p. 1553-1560, Vol. 48, No. 5
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.5.1553-1560.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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