Genetic and non-genetic factors influencing efavirenz population pharmacokinetics among human immunodeficiency virus-1-infected children in Ethiopia

Abstract

Despite the potential for efavirenz (EFV) to be an effective alternative antiretroviral agent, its sources of wide inter- and intra-individual pharmacokinetic (PK) variability are not well-characterized in children. We investigated the effects of genetic and non-genetic factors, including demographic, treatment duration, baseline clinical, and biochemical characteristics, on the PKs of EFV through population-PK modeling. Antiretroviral therapy (ART) naïve HIV infected children, 3-16 years (n = 100), were enrolled in Ethiopia and received EFV-based combination ART. EFV concentrations after the first dose and at steady-state collected over a span of 1 year were modeled using population-based methods. A one-compartment model with first-order absorption kinetics described the observed EFV data adequately. The CYP2B6*6 and ABCB1c.4036A>G genotypes were identified as major factors influencing EFV clearance. The typical estimates of oral clearance, volume of distribution, and absorption rate constant for typical 22 kg children with CYP2B6 *1/*1 and ABCB1c.4036G/G genotypes were 4.3 L/h, 124 L, and 0.776/h, respectively. Clearance was reduced by 28% and 72% in CYP2B6*1/*6 and CYP2B6*6/*6 genotypes, respectively. Compared to week 1, clearance was higher from weeks 8 and 12 in CYP2B6*1/*6 and CYP2B6*1/*1 genotypes, respectively. Simulations indicated that EFV 12-h concentrations were comparable across weight bands, but more than 80% of subjects with CYP2B6*6/*6 had EFV concentrations greater than 4 μg/mL. EFV PK variability among children is partly explained by body weight, treatment duration, CYP2B6*6, and ABCB1 rs3842 genotypes. Therefore, in addition to body weight, pediatric dosing of EFV should consider pharmacogenetic variability, duration of therapy, and individual treatment outcomes.

FIGURE 1

Observed efavirenz (EFV) concentrations over time since last dose stratified by day/weeks since initiation of EFV‐based antiretroviral therapy (ART).

FIGURE 2

Prediction corrected visual predictive check (pcVPC) of the final population pharmacokinetic model. The dashed and solid lines represent 5th, 50^th, and 95th percentiles of the observed and simulated data, respectively. The shaded areas represent 95% confidence interval of the 5th, 50^th, and 95th percentiles of the simulated data.

FIGURE 3

Boxplot of computed population summary statistics of the efavirenz (EFV) concentration at 12‐h after dose. The lower and upper box hinges represent interquartile range (i.e., 25th and 75th percentiles), whereas the lower and upper whiskers of the error‐bars represent 2.5th and 97.5th percentiles. The points in the middle of the boxes represent medians.