In vitro-in vivo Model for Evaluating the Antiviral Activity of Agenerase (amprenavir) in Combination with Norvir (ritonavir)

The study objective was to evaluate the pharmacodynamics of Agenerase (amprenavir) in an in vitro system, develop an exposure target for maximal viral suppression, and determine the likelihood of target attainment based on the pharmacokinetics of amprenavir and Norvir (ritonavir) in HIV-infected patients.

Population pharmacokinetic data were obtained from 13 HIV-infected patients receiving amprenavir and ritonavir in doses of 600 and 100 mg, respectively, every 12 h. A 2,500-subject Monte Carlo simulation was performed. Target attainment was also estimated for a target derived from clinical data. Maximal viral suppression (in vitro) was achieved when amprenavir free-drug concentrations remained greater than four times the 50% effective concentration (EC(50)) for 80% of the dosing interval.

At an amprenavir EC(50) of 0.03 microM, the likelihood of target attainment is 97.4%. For reduced-susceptibility isolates for which the EC(50)s are 0.05 and 0.08 microM, target attainment is 91.0 and 75.8%, respectively. For the clinical target of a trough concentration/EC(50) ratio of 5, the target attainment rates were similar.

Treatment with amprenavir and ritonavir at doses of 600 and 100 mg, respectively, twice a day provides excellent suppression of wild-type isolates and reduced-susceptibility isolates up to an EC(50) of 0.05 micro M.

Even at 0.12 microM, target attainment likelihood exceeds 50%, making this an option for patients with extensive exposure to protease inhibitors when this treatment is used with additional active antiretroviral agents.

Division of Clinical Pharmacology, Clinical Research Initiative, Albany Medical College, Albany, New York.

01/23/04