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

In the current study, researchers at GlaxoSmithKline evaluated high-dose combinations of fosamprenavir (FPV) [Lexiva] and ritonavir (RTV) [Norvir] in healthy adult subjects in order to select doses for further study in multiple protease inhibitor (PI)-experienced patients with HIV-1 infection.

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. Results and a discussion of the study appear in the March 2006 issue of Antimicrobial Agents and Chemotherapy.

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 (C(max)), 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), C(max), 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), C(max), and C(tau) were 26, 48, and 32% higher, respectively, and the values for plasma RTV AUC(0-tau), C(max), 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.

The authors conclude, "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."

03/21/06

Reference
MJ Shelton, MB Wire, Y Lou Y and others. Pharmacokinetic and safety evaluation of high-dose combinations of fosamprenavir and ritonavir. Antimicrobial Agents and Chemotherapy 50(3): 928-934.