Pharmacokinetics of Efavirenz at a High Dose of 25 Milligrams per Kilogram per Day in Children 2 to 3 Years Old

Abstract

The MONOD ANRS 12206 trial was designated to assess simplification of a successful lopinavir (LPV)-based antiretroviral treatment in HIV-infected children younger than 3 years of age using efavirenz (EFV; 25 mg/kg of body weight/day) to preserve the class of protease inhibitors for children in that age group. In this substudy, EFV concentrations were measured to check the consistency of an EFV dose of 25 mg/kg and to compare it with the 2016 FDA recommended dose. Fifty-two children underwent blood sampling for pharmacokinetic study at 6 months and 12 months after switching to EFV. We applied a Bayesian approach to derive EFV pharmacokinetic parameters using the nonlinear mixed-effect modeling (NONMEM) program. The proportion of midinterval concentrations 12 h after drug intake (C12 h) corresponding to the EFV therapeutic pharmacokinetic thresholds (1 to 4 mg/liter) was assessed according to different dose regimens (25 mg/kg in the MONOD study versus the 2016 FDA recommended dose). With both the 25 mg/kg/day dose and the 2016 FDA recommended EFV dose, simulations showed that the majority of C12 h values were within the therapeutic range (62.6% versus 62.8%). However, there were more children underexposed with the 2016 FDA recommended dose (11.6% versus 1.2%). Conversely, there were more concentrations above the threshold of toxicity with the 25 mg/kg dose (36.2% versus 25.6%), with C12 h values of up to 15 mg/liter. Only 1 of 52 children was switched back to LPV because of persistent sleeping disorders, but his C12 h value was within therapeutic ranges. A high EFV dose of 25 mg/kg per day in children under 3 years old achieved satisfactory therapeutic effective levels. However, the 2016 FDA recommended EFV dose appeared to provide more acceptable safe therapeutic profiles. (This study has been registered at ClinicalTrials.gov under identifier NCT01127204.).

Keywords: children; efavirenz; pharmacokinetics.

Copyright © 2017 American Society for Microbiology.

Figures

FIG 1

Visual inspection (Visual Predictive Check): comparisons among the 5th (lower dashed line), 50th (solid line), and 95th (upper dashed line) percentiles obtained from the model described by Salem et al. (14) and the observed data (points) for the MONOD trial.

FIG 2

EFV concentrations 12 h after drug intake (derived from Bayesian estimated individual pharmacokinetic parameters) as a function of weight. Crosses represent extensive metabolizers; circles represent slow metabolizers. The gray lines represent the C12 h thresholds in adults.

FIG 3

Simulations of EFV C12 h Bayesian concentrations as a function of weight for the 2016 FDA recommended dose (200-mg dose regimen for children weighing 7.5 kg to 15 kg) (left) and for the dose regimen (25 mg/kg) (right). Crosses represent extensive metabolizers; circles represent slow metabolizers. The gray lines represent the C12 h thresholds in adults.

FIG 4

Simulations of EFV C12 h Bayesian concentrations as a function of weight. (A) Without regard to CYP2B6 genotyping (FDA recommendations): 200 mg for children weighing 7.5 kg to 15 kg. (B) With regard to CYP2B6 genotyping (protocol P1070 research dose): for extensive metabolizers, 400 mg for children weighing 7 kg to 14 kg and 500 mg for children weighing 14 to 15 kg; for slow metabolizers, 100 mg for children weighing 7 kg to 14 kg and 150 mg for children weighing 14 to 15 kg. (C) Simulation of a more appropriate dose for extensive metabolizers: for extensive metabolizers, 300 mg for children weighing 7 kg to 15 kg; for slow metabolizers, 100 mg for children weighing 7 kg to 14 kg and 150 mg for children weighing 14 to 15 kg. Crosses represent extensive metabolizers; circles represent slow metabolizers. The gray lines represent the C12 h thresholds in adults.