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Antimicrobial Agents and Chemotherapy, March 2006, p. 928-934, Vol. 50, No. 3
0066-4804/06/$08.00+0     doi:10.1128/AAC.50.3.928-934.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Pharmacokinetic and Safety Evaluation of High-Dose Combinations of Fosamprenavir and Ritonavir

Mark J. Shelton,* Mary Beth Wire, Yu Lou, Brigette Adamkiewicz, and Sherene S. Min

GlaxoSmithKline, Research Triangle Park, North Carolina

Received 22 December 2005/ Accepted 23 December 2005

High-dose combinations of fosamprenavir (FPV) and ritonavir (RTV) were evaluated in healthy adult subjects in order to select doses for further study in multiple protease inhibitor (PI)-experienced patients infected with human immunodeficiency virus type 1. Two high-dose regimens, FPV 1,400 mg twice a day (BID) plus RTV 100 mg BID and FPV 1,400 mg BID plus RTV 200 mg BID, were planned to be compared to the approved regimen, FPV 700 mg BID plus RTV 100 mg BID, in a randomized three-period crossover study. Forty-two healthy adult subjects were enrolled, and 39 subjects completed period 1. Due to marked hepatic transaminase elevations, predominantly with FPV 1,400 mg BID plus RTV 200 mg BID, the study was terminated prematurely. For FPV 1,400 mg BID plus RTV 100 mg BID, the values for plasma amprenavir (APV) area under the concentration-time profile over the dosing interval ({tau}) at steady state [AUC(0-{tau})], maximum concentration of drug in plasma (Cmax), and plasma concentration at the end of {tau} at steady state (C{tau}) were 54, 81, and 26% higher, respectively, and the values for plasma RTV AUC(0-{tau}), Cmax, and C{tau} were 49% higher, 71% higher, and 11% lower, respectively, than those for FPV 700 mg BID plus RTV 100 mg BID. For FPV 1,400 mg BID plus RTV 200 mg BID, the values for plasma APV AUC(0-{tau}), Cmax, and C{tau} were 26, 48, and 32% higher, respectively, and the values for plasma RTV AUC(0-{tau}), Cmax, and C{tau} increased 4.15-fold, 4.17-fold, and 3.99-fold, respectively, compared to those for FPV 700 mg BID plus RTV 100 mg BID. FPV 1,400 mg BID plus RTV 200 mg BID is not recommended due to an increased rate of marked hepatic transaminase elevations and lack of pharmacokinetic advantage. FPV 1,400 mg BID plus RTV 100 mg BID is currently under clinical evaluation in multiple PI-experienced patients.

* Corresponding author. Mailing address: GlaxoSmithKline, 5 Moore Drive, Research Triangle Park, NC 27709. Fax: (919) 315-4276. Phone: (919) 483-5062. E-mail: Mark.J.Shelton{at}GSK.com.

Antimicrobial Agents and Chemotherapy, March 2006, p. 928-934, Vol. 50, No. 3
0066-4804/06/$08.00+0     doi:10.1128/AAC.50.3.928-934.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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