Pharmacokinetics of Antiretroviral Drug Varies With Formulation in the Target Population of Children With HIV-1

Kasirye, P; Kendall, L; Adkison, K K; Tumusiime, C; Ssenyonga, M; Bakeera-Kitaka, S; Nahirya-Ntege, P; Mhute, T; Kekitiinwa, A; Snowden, W; Burger, D M; Gibb, D M; Walker, A S
February 2012
Clinical Pharmacology & Therapeutics;Feb2012, Vol. 91 Issue 2, p272
Academic Journal
The bioequivalence of formulations is usually evaluated in healthy adult volunteers. In our study in 19 HIV-1-infected Ugandan children (1.8-4 years of age, weight 12 to <15 kg) receiving zidovudine, lamivudine, and abacavir solutions twice a day for ≥24 weeks, the use of scored tablets allowed comparison of plasma pharmacokinetics of oral solutions vs. tablets. Samples were collected 0, 1, 2, 4, 6, 8, and 12 h after each child's last morning dose of oral solution before changing to scored tablets of Combivir (coformulated zidovudine + lamivudine) and abacavir; this was repeated 4 weeks later. Dose-normalized area under curve (AUC)0-12 and peak concentration (Cmax) for the tablet formulation were bioequivalent with those of the oral solution with respect to zidovudine and abacavir (e.g., dose-normalized geometric mean ratio (dnGMR) (tablet:solution) for zidovudine and abacavir AUC0-12 were 1.01 (90% confidence interval (CI) 0.87-1.18) and 0.96 (0.83-1.12), respectively). However, lamivudine exposure was ~55% higher with the tablet formulation (AUC0-12 dnGMR = 1.58 (1.37-1.81), Cmax dnGMR = 1.55 (1.33-1.81)). Although the clinical relevance of this finding is unclear, it highlights the impact of the formulation and the importance of conducting bioequivalence studies in target pediatric populations.


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