Genetic and Non-genetic Factors Influencing Efavirenz Population Pharmacokinetics Among HIV-infected Children in Ethiopia.

Despite the potential for efavirenz (EFV) to be an effective alternative antiretroviral agent, its sources of wide inter- and intra-individual pharmacokinetic (PK) variability is 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 PK of EFV through population-PK modeling. ART naïve HIV infected children, 3-16 years (n=100), were enrolled in Ethiopia and received EFV based antiretroviral therapy (cART). EFV concentrations after the first dose and at steady state collected over a span of one year were modelled 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 week 8 and 12 in CYP2B6*1/*6 and CYP2B6*1/*1 genotypes respectively. Simulations indicated that EFV 12-hour concentrations were comparable across weight bands but > 80% of subjects with CYP2B6*6/*6 had EFV concentrations > 4 μg/mL. EFV pharmacokinetics 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.