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Pharmacokinetic and Pharmacodynamic Analysis of Amprenavir-Containing Combination Therapy in HIV-1-Infected Children

From Worldwide Clinical Pharmacology (Dr Stein, Dr Johnson), Statistics (Y. Lou), GlaxoSmithKline, Research Triangle Park, North Carolina; Clinical Virology, GlaxoSmithKline, Stevenage, United Kingdom (S Randall); University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina (Dr Stein); and Hôpital Necker/Enfants Malades, Paris, France (Dr Blanche).

Several factors influence the antiviral response to antiretroviral therapy. In this pharmacokinetic and pharmacodynamic analysis, the relationship of drug exposure, demographics, and cotherapy measures to antiviral response in a cohort of largely treatment-experienced children treated with amprenavir and nucleoside reverse transcriptase inhibitors was examined. Multiple pharmacodynamic and demographic factors were examined, but only the minimum plasma concentration (C_min)/protein-binding-adjusted 50% inhibitory drug concentration (IC₅₀) ratio and whether individuals received 2 versus fewer than 2 nucleosides to which their viral isolates were susceptible were associated with the magnitude of the time-weighted average change in HIV-1 RNA log₁₀ copies/mL from baseline (AAUCMB). In multivariate logistic regression analysis, only the C_min/IC₅₀ ratio was independently associated with having a 1 log₁₀ AAUCMB decline. The probability in the study population of having a 1log₁₀ AAUCMB was 50% and 85% at C_min/IC₅₀ ratios of 1 and 4, respectively. Of the multiple factors examined, only the C_min/IC₅₀ ratio was a significant predictor of antiviral response in the first 8 weeks on amprenavir-containing combination antiretroviral therapy.

Key Words: Antiretroviral therapy • amprenavir • protease inhibitors • nucleoside reverse transcriptase inhibitors • HIV • pharmacokinetics • pediatrics

Address for reprints: Daniel S. Stein, MD, Clinical Discovery and Human Pharmacology, Aventis, 1041 Route 202/206N, BWM-203A, Bridgewater, NJ 08807.

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