Background:  Pediatric studies suggested that the actual recommended efavirenz (EFV) dosage produced insufficient plasma concentrations in children. In the context of a phase II trial on once-a-day pediatric HAART, the aims of this study were to describe EFV concentration-time courses in treatment naïve children, to study the effect of age and body weight on EFV pharmacokinetics and to test relationships between doses, plasma concentrations, and efficacy.

Methods:  EFV concentrations were measured in 48 children after 2 weeks of didanosine/lamivudine/EFV treatment, and samples were available in 9 of 48 children between month 2 and 5 of treatment. A total of 200 EFV plasma concentrations were collected and a population pharmacokinetic model was developed with NONMEM. The influence of individual characteristics was tested using a likelihood ratio test. Estimated minimal (C_min), maximal (C_max) concentrations, area under the curve (AUC) were correlated to the decrease in HIV-1 RNA levels after 3 months of treatment. The threshold C_min (and AUC) improving efficacy was determined. The target minimal concentration of 4 mg/L was considered for toxicity. An optimized dosing schedule was simulated in order that the higher percentage of children is in the effective and not toxic concentrations interval.

Results:  EFV pharmacokinetics was best described by a one-compartment model with first order absorption and elimination. Mean EFV apparent elimination clearance and volume of distribution were respectively 0.211 L/h/kg and 4.48 L/kg. The elimination clearance significantly decreased with age. With the recommended doses given to 46 out of the 48 children, 19% had a minimal concentration below 1 mg/L; they were 44% under this limit in the <15-kg children. A significant higher percentage of children with C_min >1.1 mg/L (or AUC >51 mg/L.h) had a viral load decrease greater than 2 log₁₀ copies/mL after 3 months of treatment, compared to children below these values.

Conclusions:  To optimize the percentage of children with a C_min between 1.1 and 4 mg/L, children should receive the following once-daily EFV dose:  25 mg/kg from 2 to 6 years, 15 mg/kg from 6 to 10 years, and 10 mg/kg from 10 to 15 years. These assumptions should be prospectively confirmed.