Plasma Amprenavir Pharmacokinetics and Tolerability following Administration of 1,400 Milligrams of Fosamprenavir Once Daily in Combination with either 100 or 200 Milligrams of Ritonavir in Healthy Volunteers

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Abstract
Once-daily (QD) fosamprenavir (FPV) at 1,400 mg boosted with low-dose ritonavir (RTV) at 200 mg is effective when it is used in combination regimens for the initial treatment of human immunodeficiency virus infection. Whether a lower RTV boosting dose (i.e., 100 mg QD) could ensure sufficient amprenavir (APV) concentrations with improved safety/tolerability is unknown. This randomized, two 14-day-period, crossover pharmacokinetic study compared the steady-state plasma APV concentrations, safety, and tolerability of FPV at 1,400 mg QD boosted with either 100 mg or 200 mg of RTV QD in 36 healthy volunteers. Geometric least-square (GLS) mean ratios and the associated 90% confidence intervals (CIs) were estimated for plasma APV maximum plasma concentrations ( C max ), the area under the plasma concentration-time curve over the dosing period (AUC 0-τ ), and trough concentrations ( C τ ) during each dosing period. Equivalence between regimens (90% CIs of GLS mean ratios, 0.80 to 1.25) was observed for the plasma APV AUC 0-τ (GLS mean ratio, 0.90 [90% CI, 0.84 to 0.96]) and C max (0.97 [90% CI, 0.91 to 1.04]). The APV C τ was 38% lower with RTV at 100 mg QD than with RTV at 200 mg QD (GLS mean ratio, 0.62 [90% CI, 0.55 to 0.69]) but remained sixfold higher than the protein-corrected 50% inhibitory concentration for wild-type virus, with the lowest APV C τ observed during the 100-mg QD period being nearly threefold higher. The GLS mean APV C τ was 2.5 times higher than the historical C τ for unboosted FPV at 1,400 mg twice daily. Fewer clinical adverse drug events and smaller increases in triglyceride levels were observed with the RTV 100-mg QD regimen. Clinical trials evaluating the efficacy and safety of FPV at 1,400 mg QD boosted by RTV at 100 mg QD are now under way with antiretroviral therapy-naïve patients.

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