Pharmacokinetics of Nevirapine in 3- to 6-kg, HIV-infected Infants Taking Pediatric Fixed-dose Combination Tablets
Veronica Mulenga*1, Q Fillekes2, D Kabamba1, C Kankasa1, M Thomason3, A Ferrier3, S Walker3, D Gibb3, C Chintu1, and D Burger2
1Univ Teaching Hosp, Lusaka, Zambia; 2Radboud Univ Nijmegen Med Ctr, Nijmegen, The Netherlands; and 3Med Res Council, London, UK
Background: We previously reported 12-hour
pharmacokinetic profiles of nevirapine (NVP), stavudine (d4T), and lamivudine
(3TC) in HIV-infected African children after taking fixed-dose combination
antiretroviral tablets (Triomune Baby—50 mg NVP, 6 mg d4T, 30 mg 3TC) and
Junior (double Baby dose). However, this study included only 2 children with
body weight 3 to 6 kg; we therefore undertook pharmacokinetic evaluations in 14
additional children weighing 3 to 6 kg.
Methods: We included 16 HIV-infected children
aged 1 month or older, weighing 3 to 6 kg, and fulfilling WHO criteria for
initiating treatment. Children were admitted for a 12-hour pharmacokinetic
sampling session at least 4 weeks after starting treatment. Samples were taken
at t = 0, 2, 6, and 12 hours after observed intake of 1 tablet Triomune Baby. NVP
plasma concentrations were determined using high-performance liquid
chromatography with ultraviolet detection. Pharmacokinetic parameters (AUC, Cmax,
Cmin) were determined using noncompartmental methods.
Results: One child was excluded because of
nonadherence. The median (interquartile range) age, body weight and daily NVP
dose of the remaining 15 children (8 girls; 7 boys) were 5.3 (4.1 to 8.4)
months, 5.3 (4.2 to 5.5) kg, and 348 (324-386) mg/m2, respectively.
The mean (standard deviation) NVP AUC0-12h, Cmax and Cmin
were 78.7 (30.2) h.mg/L, 8.1 (2.4) mg/L, and 4.9 (2.6) mg/L, respectively.
These values are higher than reported in adults, but are 15 to 20% lower than
observed previously in Zambian children with body weight >6 kg taking these
pediatric fixed-dose combinations. Of some concern, 4 of the 15 (27%) children
with body weight 3 to 6 kg had a subtherapeutic NVP Cmin (defined as
<3.0 mg/L) compared to only 3 of 63 (5%) children with body weight >6 kg
(p = 0.02, Exact Test). While children aged <5 months appeared to
have a higher risk for a subtherapeutic NVP Cmin than those 5 months
or older, numbers were too small to reach statistical significance—3 of 6 (50%)
vs 1 of 9 (11%), p = 0.24; note, dose range in those <5 months was
324 to 406 mg/m2.
Conclusions: Exposure to NVP in African HIV-infected
children with low body weight taking fixed-dose combination tablets appears on
average to be adequate, but due to large intersubject variability a relatively
high proportion of children had subtherapeutic NVP Cmin levels,
particularly those aged <5 months. As infants <5 months may be at risk
for low NVP exposure for only a short time after initiating treatment, the
clinical consequences of such low Cmin may be minor, but require