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Antimicrobial Agents and Chemotherapy, February 2008, p. 534-538, Vol. 52, No. 2
0066-4804/08/$08.00+0     doi:10.1128/AAC.00724-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Pharmacokinetic Interaction between Fosamprenavir-Ritonavir and Rifabutin in Healthy Subjects{triangledown}

Susan L. Ford,* Ya-Chi Chen,{dagger} Yu Lou, Julie Borland, Sherene S. Min, Geoffrey J. Yuen, and Mark J. Shelton

Clinical Pharmacology and Discovery Medicine, GlaxoSmithKline, Research Triangle Park, North Carolina

Received 5 June 2007/ Returned for modification 27 August 2007/ Accepted 8 November 2007

Rifabutin (RFB) is administered for treatment of tuberculosis and Mycobacterium avium complex infection, including use for patients coinfected with human immunodeficiency virus (HIV). Increased systemic exposure to RFB and its equipotent active metabolite, 25-O-desacetyl-RFB (dAc-RFB), has been reported during concomitant administration of CYP3A4 inhibitors, including ritonavir (RTV), lopinavir, and amprenavir (APV); therefore, a reduction in the RFB dosage is recommended when it is coadministered with these protease inhibitors. Fosamprenavir (FPV), the phosphate ester prodrug of the HIV type 1 protease inhibitor APV, is administered either with or without RTV. A randomized, open-label, two-period, two-sequence, balanced, crossover drug interaction study was conducted with 22 healthy adult subjects to compare steady-state plasma RFB pharmacokinetic parameters during concomitant administration of FPV-RTV (700/100 mg twice a day [BID]) with a 75%-reduced RFB dose (150 mg every other day [QOD]) to the standard RFB regimen (300 mg once per day [QD]) by geometric least-squares mean ratios. Relative to results with RFB (300 mg QD), coadministration of dose-adjusted RFB with FPV-RTV resulted in an unchanged RFB area under the concentration-time curve for 0 to 48 h (AUC0-48) and a 14% decrease in the maximum concentration of drug in plasma (Cmax), whereas the AUC0-48 and Cmax of dAc-RFB were increased by 11- and 6-fold, respectively, resulting in a 64% increase in the total antimycobacterial AUC0-48. Relative to historical controls, the plasma APV AUC from 0 h to the end of the dosing interval (AUC0-{tau}) and Cmax were increased ~35%, and the concentration at the end of the dosing interval at steady state was unchanged following coadministration of RFB with FPV-RTV. The safety profile of the combination of RFB and FPV-RTV was consistent with previously described events with RFB or FPV-RTV alone. Based on the results of this study, a reduction in the RFB dose by ≥75% (to 150 mg QOD or three times per week) is recommended when it is coadministered with FPV-RTV (700/100 mg BID).

* Corresponding author. Mailing address: GlaxoSmithKline CPDM, Five Moore Drive, RTP, NC 27709. Phone: (919) 483-0392. Fax: (919) 483-6380. E-mail: susan.l.ford{at}gsk.com

{triangledown} Published ahead of print on 3 December 2007.

{dagger} Present address: Asubio Pharmaceuticals, Inc., Rochelle Park, NJ.

Antimicrobial Agents and Chemotherapy, February 2008, p. 534-538, Vol. 52, No. 2
0066-4804/08/$08.00+0     doi:10.1128/AAC.00724-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Maa, M.-T., Leibert, E. (2009). ACQUIRED RIFAMYCIN MONORESISTANCE AND PROTEASE INHIBITORS DURING IN-PATIENT DIRECTLY-OBSERVED THERAPY FOR HIV AND MYCOBACTERIUM TUBERCULOSIS CO-INFECTION. Chest Meeting 136: 50S-50S [Abstract]  


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