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Antimicrobial Agents and Chemotherapy, January 2003, p. 118-123, Vol. 47, No. 1
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.1.118-123.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Steady-State Pharmacokinetics of Amprenavir Coadministered with Ritonavir in Human Immunodeficiency Virus Type 1-Infected Patients

Cecile Goujard,1 Isabelle Vincent,2 Jean-Luc Meynard,1 Nathalie Choudet,2 Diane Bollens,3 Cyril Rousseau,1 Didier Demarles,4 Catherine Gillotin,4 Roselyne Bidault,4 and Anne-Marie Taburet2*

Internal Medicine Department,1 Clinical Pharmacy, Bicetre Hospital,2 Department of Infectious Diseases, St. Antoine Hospital, Assistance Publique-Hopitaux de Paris, Paris,3 Glaxo Wellcome Laboratory, Marly-le-Roi, France4

Received 2 January 2002/ Returned for modification 18 August 2002/ Accepted 6 October 2002

The protease inhibitor (PI) ritonavir is used as a strong inhibitor of cytochrome P450 3A4, which boosts the activities of coadministered PIs, resulting in augmented plasma PI levels, simplification of the dosage regimen, and better efficacy against resistant viruses. The objectives of the present open-label, multiple-dose study were to determine the steady-state pharmacokinetics of amprenavir administered at 600 mg twice daily (BID) and ritonavir administered at 100 mg BID in human immunodeficiency virus type 1 (HIV-1)-infected adults treated with different antiretroviral combinations including or not including a nonnucleoside reverse transcriptase inhibitor (NNRTI). Nineteen patients completed the study. The steady-state mean minimum plasma amprenavir concentration (Cmin,ss) was 1.92 µg/ml for patients who received amprenavir and ritonavir without an NNRTI and 1.36 µg/ml for patients who received amprenavir and ritonavir plus efavirenz. For patients who received amprenavir-ritonavir without an NNRTI, the steady-state mean peak plasma amprenavir concentration (Cmax,ss) was 7.12 µg/ml, the area under the concentration-time curve from 0 to 10 h (AUC0-10) was 32.06 µg · h/ml, and the area under the concentration-time curve over a dosing interval (12 h) at steady-state (AUCss) was 35.74 µg · h/ml. Decreases in the mean values of Cmin,ss (29%), Cmax,ss (42%), AUC0-10 (42%), and AUCss (40%) for amprenavir occurred when efavirenz was coadministered with amprenavir-ritonavir. No unexpected side effects were observed. As expected, coadministration of amprenavir with ritonavir resulted in an amprenavir Cmin,ss markedly higher than those previously reported for the marketed dose of amprenavir. When amprenavir-ritonavir was coadministered with efavirenz, amprenavir-ritonavir maintained a mean amprenavir Cmin,ss above the mean 50% inhibitory concentration of amprenavir previously determined for both wild-type HIV-1 isolates and HIV-1 strains isolated from PI-experienced patients. These data support the use of low-dose ritonavir to enhance the level of exposure to amprenavir and increase the efficacy of amprenavir.

* Corresponding author. Mailing address: Clinical Pharmacy, Bicetre Hospital, 78 rue du General Leclerc, 94270 Le Kremlin Bicetre, France. Phone: (33) 1 45 21 29 57. Fax: (33) 1 45 21 28 60. E-mail: anne-marie.taburet{at}bct.ap-hop-paris.fr.

Antimicrobial Agents and Chemotherapy, January 2003, p. 118-123, Vol. 47, No. 1
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.1.118-123.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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