Abacavir and Metabolite Pharmacokinetics in HIV-1-Infected Children and Adolescents

Abstract

Objectives Abacavir (ABC) oral clearance, adjusted for body size, is approximately 2 times higher for children than adults with a corresponding difference in dose regimens. However, there are limited data available in the adolescent population. The pharmacokinetics (PKs) of ABC and primary metabolites were determined in HIV-1–infected children and adolescents to evaluate age and patient characteristics as a basis for adjusting ABC dose regimens and to assess the influence of metabolite formation on PK parameters. Methods Pediatric subjects 9–18 years of age receiving antiretroviral therapy for HIV-1 infection were stratified by Tanner stage and given a single 8 mg/kg dose of ABC oral solution. Blood samples (n = 10) were obtained over 8 hours and measured for ABC, glucuronide, and carboxylate metabolites using high-performance liquid chromatography. PK parameters for children (Tanner stages 1–2; TS1) and adolescents (Tanner stages 3–5; TS2) were compared. Results Twenty-five subjects were enrolled. ABC mean (range) maximum concentration (Cmax; μg/mL), area under the curve (μg·hr/mL), half-life (hours), and apparent clearance (CL/F; mL/min per kg) for TS1 and TS2 were 3.5 (1.2–5.6) vs 3.4 (1.8–5.9), 8.0 (2.1– 18.6) vs 8.9 (3.1–17.2), 1.3 (0.7–2.5) vs 1.4 (0.9–1.9), and 22.1 (7.0– 59.2) vs 18.4 (7.7–42.9) and not significantly different. Age, Tanner stage, and sex were not correlated with ABC clearance by univariate analysis. The ratios of metabolites to ABC area under the curve were correlated with ABC clearance as were the ratios of metabolites to ABC concentrations at the 6-hour time point. Conclusions ABC oral clearance in HIV-1-infected pediatric patients does not change during puberty, is similar to younger children, and is higher than previously published in adults. Therefore, dosing adolescents as adults should be reexamined. Intersubject PK variability is substantial and is not correlated with body size or age but more likely due to differences in metabolite formation that may be genetic in origin.

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