Population Pharmacokinetics Analysis To Inform Efavirenz Dosing Recommendations in Pediatric HIV Patients Aged 3 Months to 3 Years

Efavirenz (EFV) is a nonnucleoside reverse transcriptase inhibitor approved worldwide for the treatment of HIV in adults and children over 3 years of age or weighing over 10 kg. Only recently EFV was approved in children over 3 months and weighing at least 3.5 kg in the United States and the European Union. The objective of this analysis was to support the selection of an appropriate dose for this younger pediatric population and to explore the impact of CYP2B6 genetic polymorphisms on EFV systemic exposures. A population pharmacokinetic (PPK) model was developed using data from three studies in HIV-1-infected pediatric subjects (n = 168) and one study in healthy adults (n = 24). The EFV concentration-time profile was best described by a two-compartment model with first-order absorption and elimination. Body weight was identified as a significant predictor of efavirenz apparent clearance (CL), oral central volume of distribution (V-C), and absorption rate constant (K-a). The typical values of efavirenz apparent CL, V-C, oral peripheral volume of distribution (V-P), and K-a for a reference pediatric patient were 4.8 liters/h (4.5 to 5.1 liters/h), 84.9 liters (76.8 to 93.0 liters), 287 liters (252.6 to 321.4 liters), and 0.414 h(-1) (0.375 to 0.453 h(-1)), respectively. The final model was used to simulate steady-state efavirenz concentrations in pediatric patients weighing< 10 kg to identify EFV doses that produce comparable exposure to adult and pediatric patients weighing >= 10 kg. Results suggest that administration of EFV doses of 100 mg once daily (QD) to children weighing >= 3.5 to< 5 kg, 150 mg QD to children weighing >= 5 to< 7.5 kg, and 200 mg QD to children weighing >= 7.5 to< 10 kg produce exposures within the target range. Further evaluation of the impact of CYP2B6 polymorphisms on EFV PK showed that the identification of CYP2B6 genetic status is not predictive of EFV exposure and thus not informative to guide pediatric dosing regimens.