Background:  Use of once daily efavirenz (EFV) -based HAART therapy in HIV-infected infants is limited by formulation availability and a lack of EFV pharmacokinetic and dosing information. We evaluated the pharmacokinetics of EFV solution in patients <3 years of age (Group 1) and compared them to pharmacokinetics seen in older pediatric patients (Groups 2 and 3).

Methods:  EFV pharmacokinetic data were analyzed from a prospective study, IMPAACT /PACTG P1021, that enrolled 43 HIV-infected subjects ages 90 days to 21 years. In the 6 subjects <3 years, an initial dose of 390 mg (<10 kg) or 600 mg (>10 kg) EFV solution was given once daily with emtricitabine (FTC) and didanosine (ddI). Older subjects received EFV, 250 to 600 mg, solution or capsules based on weight. An intensive 24-hour pharmacokinetic evaluation was performed after 2 weeks of therapy. Dose modifications were performed for subjects with AUC outside the range of 35 to 120 µg*h/mL. Repeat intensive pharmacokinetics evaluations were performed for subjects with dose or formulation modifications. EFV pharmacokinetics were assessed by non-compartmental methods.

Results:  The median ages in the 3 groups were 0.5, 6.3, and 18 years. Of the Group 1 subjects, 2 (33%) had dose modifications, 1 due to high (AUC = 269) and other low (AUC = 28.8) EFV exposure; 3 Group 1 subjects had dose increases to 600 at weight >10 kg with repeat AUC that ranged from 8 to 150. EFV apparent clearance (CL/F) was greater (p <0.003) in Group 1 than Groups 2 and 3. The median EFV pharmacokinetic parameters with the solution formulation are shown in the table. Intermittent pre-dose trough concentrations collected during up to 2 years of treatment were consistent with the intensive pharmacokinetic study results. The dose normalized EFV AUC and C_max for the solution formulation were approximate 80% of the values obtained with the capsule formulation.

Conclusions:  EFV pharmacokinetics demonstrates pronounced age effects with apparent clearance much greater in young infants than older children. High EFV dose requirements and pharmacokinetic variability in infants will require additional pharmacokinetic studies to determine appropriate EFV dosing strategies.