Background:  Due in part to lack of affordable antiretrovirals and convenience of a fixed-dose combination tablet, a large number of HIV-infected children in Thailand receive an adult fixed-dose combination of stavudine (d4T)/lamivudine (3TC)/nevirapine (NVP) (30/150/200 mg/tablet), which often requires breaking the tablet to obtain an appropriate dose. Previous studies suggested satisfactory NVP exposure and good clinical response in this setting, but fixed-dose combination tablets designed for children are urgently needed. A new pediatric chewable fixed-dose combination tablet of d4T/3TC/NVP (7/30/50 mg/tablet) has been developed by the Thailand Government Pharmaceutical Organization. Limited data on NVP exposure in children using different fixed-dose combination are available. We assessed NVP pharmacokinetics in Thai children receiving either adult (GPOvir^®S30) or pediatric (GPOvir^®S7) fixed-dose combination.

Methods:  NVP concentration information from 44 children (average age 8.6±2.9 yrsrs and weight 24.3±8.3 kg) was combined from 2 clinical studies. NVP plasma level results from 9 children enrolled in IMPAACT P1056, an ongoing pharmacokinetic study comparing GPOvir^®S7 with the standard liquid formulations, who had intensive pharmacokinetic sampling collected pre-dose, and 0.5, 1, 2, 4, 8, and 12 hours post-dose were combined with data from a separate study of 35 children who received GPOvir^®S30 and had pharmacokinetic sampling collected pre-dose, and 2, 6 hours post-dose. Pharmacokinetic data were analyzed using a 1-compartment model and population approach with the program NONMEM. Formulation differences in absorption were assessed by changes in objective function.

Results:  Independent of formulation, median NVP clearance was 0.081 L/h/kg and volume of distribution 1.79 L/kg. NVP GPOvir^®S30 profiles exhibited a slower rate of absorption (p <0.001), but had comparable bioavailability (p >0.20) to GPOvir^®S7. Average NVP AUC was 75.5±40.5 and 81.1±34.7 µg·hr/mL for GPOvir^®S30 and GPOvir^®S7, respectively. Due to a “flatter” concentration profile, median pre-dose NVP concentrations were higher with GPOvir^®S30 compared to GPOvir^®S7, 6.0 µg/mL (3.4 to 24.0) vs 4.3 µg/mL (3.0 to 10.0), p = 0.06. All children achieved a pre-dose NVP concentration above the recommend target therapeutic threshold of 3.0 µg/mL.

Conclusions:  NVP pharmacokinetic parameters in Thai children using fixed-dose combination tablets containing either NVP 200 mg or 50 mg were within the range observed in prior pediatric studies. No clinically significant differences in NVP pharmacokinetics were observed between the 2 different strength NVP formulations.