Background:  To achieve therapeutic concentrations across the pediatric age continuum, nevirapine (NVP) is dosed based on body surface area (150 to 200 mg/m²) or weight and age (7 mg/kg <8 years and 4 mg/kg ≥8 years). In resource limited settings, these dosing guidelines are too complex for wide spread implementation. The World Health Organization (WHO) has developed a simple weight-band dosing algorithm suitable for these settings, but the ability of this strategy to achieve therapeutic NPV exposure has not been assessed. The objective of this study was to determine the NVP exposure expected from the WHO dosing guidelines and compared it to Food and Drug Administration (FDA) dosing.

Methods:  NVP pharmacokinetic data across 5 Pediatric AIDS Clinical Trials Group (PACTG) studies conducted in the United States were combined with data from Zambia (CHAPAS) and Thailand (IMPAACT P1056), totaling 565 pediatric subjects. The AUC and C_min with WHO dosing using 50- to 60-mg tablets were determined from the ratio of doses (parameter x WHO Dose/Study Dose). The frequency of sub-therapeutic concentrations (C_min <3 µg/mL or AUC <48 µg·h/mL) and supra-therapeutic concentrations, 120 µg·h/mL (2x average) were determined. A Monte Carlo simulation was performed using a population pharmacokinetic model that included age, weight, ritonavir (RTV) use, and CYP 2B6 genotype. Using weight-band dosing, 7720 pediatric NVP concentration profiles were simulated.

Results:  NVP AUC and C_min were similar across the 3 countries. Excluded from the analysis were 94 subjects receiving RTV and 88 subjects outside the WHO dosing weight groups (<5 or >30 kg). The median (IQR) dose, C_min and AUC were 174 mg/m² (162 to 187), 5.7 µg/mL (3.8 to 8.0), and 77.7 µg·h/mL (55.8 to 107.2) for WHO 50-mg dosing and 153 mg/m² (112 to 172), 4.6 µg/mL (3.0 to 6.9), and 62.2 µg·h/mL (45.1 to 90.8) for FDA dosing. WHO dosing exceeded C_min and AUC targets in 85% and 84% of subjects. The FDA dose met these targets in only 75% and 72% of subjects. The frequency of AUC >120 was higher with WHO than FDA dosing (18% vs 10%). Increasing the NVP tablet dose from 50 to 60 mg reduced the frequency of sub-therapeutic levels by 5%, but increased supra-therapeutic levels by 12%. Monte Carlo simulation exceeded target AUC and C_min in 77% of virtual patients.

Conclusions:  The WHO weight-band dosing of NVP achieves therapeutic concentrations in a greater portion of subjects than the FDA dose of 4 to 7 mg/kg. The 50-mg tablet strength maximizes the therapeutic index. WHO weight-band dosing should be used in resource-limited settings.