Nevirapine exposure with WHO pediatric weight band dosing: enhanced therapeutic concentrations predicted based on extensive international pharmacokinetic experience

Abstract

Nevirapine (NVP) is a nonnucleoside reverse transcriptase inhibitor (NNRTI) used worldwide as part of combination antiretroviral therapy in infants and children to treat HIV infection. Dosing based on either weight or body surface area has been approved by the U.S. Food and Drug Administration (FDA) but can be difficult to implement in resource-limited settings. The World Health Organization (WHO) has developed simplified weight band dosing for NVP, but it has not been critically evaluated. NVP pharmacokinetic data were combined from eight pediatric clinical trials (Pediatric AIDS Clinical Trials Group [PACTG] studies 245, 356, 366, 377, 403, 1056, and 1069 and Children with HIV in Africa Pharmacokinetics and Adherence of Simple Antiretroviral Regimens [CHAPAS]) representing subjects from multiple continents and across the pediatric age continuum. A population pharmacokinetic model was developed to characterize developmental changes in NVP disposition, identify potential sources of NVP pharmacokinetic variability, and assess various pediatric dosing strategies and their impact on NVP exposure. Age, CYP2B6 genotype, and ritonavir were independent predictors of oral NVP clearance. The Triomune fixed-dose tablet was an independent predictor of bioavailability compared to the liquid and other tablet formulations. Monte Carlo simulations of the final model were used to assess WHO weight band dosing recommendations. The final pharmacokinetic model indicated that WHO weight band dosing is likely to result in a percentage of children with NVP exposure within the target range similar to that obtained with FDA dosing. Weight band dosing of NVP proposed by the WHO has the potential to provide a simple and effective dosing strategy for resource limited settings.

Fig 1

(A) Goodness-of-fit plot. NVP concentrations from the study were compared to NONMEM individual predicted concentrations. (B) Visual predictive plots for an NVP population PK model for patients not taking RTV or Triomune and with active copies of the CYP2B6 gene (extensive metabolizers). Solid lines represent median concentrations, and dashed lines represent 97.5 and 2.5 percentiles from a Monte Carlo simulation of the final model.

Fig 2

Population PK model results. (A) Estimated NVP apparent clearance (clearance/bioavailability) versus age for patients not taking RTV or Triomune and with active copies of the CYP2B6 gene (extensive metabolizers). The solid line represents the population-based apparent clearance profile, which was derived using the allometrically scaled median weight for each age group (CDC 50th-percentile weight). (B) Estimated NVP apparent clearance versus age.

Fig 3

CYP2B6 active alleles compared to deviation from expected clearance (eta for clearance) in a population PK base model (allometric weight was the only covariate).

Fig 4

Monte Carlo simulations with WHO weight band dosing recommendations. (A) FDA dose (150 mg/m² with a maximum of 200 mg, twice daily) compared to WHO weight band dosing for NVP exposure (area under the curve) and 12-h trough concentrations (C₁₂). (B) Median drug exposure (area under the curve) for WHO weight banding dosing. Data are medians and interquartile ranges of NVP AUC (μg · h/ml). Target AUC levels are represented by dashed lines (42 to 108 μg · h/ml). (C) Median 12-h concentrations (trough levels) for WHO weight band dosing. Data are medians and interquartile ranges of NVP concentration (μg/ml). Goal trough concentrations are represented by dashed lines (3 to 7.6 μg/ml). (D) WHO weight band dosing for the overall study distribution of CYP2B6 genotype compared to a population of poor metabolizers (PM) (CYP2B6 516 TT). Area under the curve (AUC) and C₁₂ (trough concentrations) are given.