Background:  Pediatric AIDS Clinical Trials Group (PACTG) 1020 is a prospective phase I/II open-label area-under the concentration time curve (AUC)-controlled study to determine the safety, pharmacokinetics, and optimal dose of once-daily atazanavir (ATV) powder and capsules with and without ritonavir (RTV) boosting in HIV-infected children receiving ≥ 2 nucleoside reverse transcriptase inhibitors (NRTI).

Methods:  ART-naïve and -experienced children with HIV RNA > 5000 copies/mL and ATV phenotypic susceptibility (< 10-fold wild type IC₅₀) are eligible. There are 8 study groups:  in groups 1 to 4 we are evaluating unboosted and in groups 5 to 8 boosted ATV. Groups 5 (91 days to 2 years old) and 6 (> 2 years to 13 years) are evaluating ATV powder; groups 7 (> 2 years to 13 years) and 8 (> 13 years to 21 years) ATV capsules. The starting dose is ATV 310 mg/m² daily (maximum 800 mg) and RTV 100 mg/m² daily (maximum 100 mg). Dose acceptance criteria are:  AUC of ≥ 30 µg•h/mL and minimum ATV concentration ≥ 0.06 µg/mL in 4 of the first 5 patients in a group, and no AUC <15 µg•hr/mL. If criteria are met, 5 more patients are enrolled at the same dose and re-evaluated. If criteria are not met, ATV starting dose is modified accordingly in the next 5 patients. We obtained 24-hour pharmacokinetic data from all patients at weeks 1 and 56, and repeated 2 weeks after any pharmacokinetic-guided dosage adjustment.

Results:  Week 1 pharmacokinetic studies have been completed by 15 children (119 days to 12.1 years). In the youngest group (group 5, median age 0.8 years, n = 5), median AUC and oral clearance (CL/F) were 27.7 µg•h/mL and 12.4 L/h/m². In older children receiving powder (group 6, median age 4.1 years, n = 7), the median AUC and CL/F were 50.3 mcg•h/mL and 6.2 L/h/m², while in older children receiving capsules (group 7, median age 10.5 years, n = 3) they were 120 µg•h/mL and 2.9 L/h/m². For the overall group (n = 15), median (range) pharmacokinetic parameters are:  AUC, 52 µg•hr/mL (7.4 to 134 µg•hr/mL); C_max, 4.8 µg/mL (0.77 to 12.9 µg/mL); 24-hour post-dose, 0.9 µg/mL (0.13 to 3.4 µg/mL); and CL/F, 5.4 L/h/m² (2.2 to 35.8 L/h/m²). This compares with AUC, 18.9 µg•hr/mL (3.4 to 44.9 µg•hr/mL) and CL/F, 14 L/h/m² (7 to 102.3 L/h/m²) in children (n = 20) receiving unboosted ATV (310 mg/m²). A boosting dose of RTV provided children with 2.8 fold higher AUC and 2.6-fold lower CL/F of ATV than that seen with the same unboosted dose.

Conclusions:  ATV CL/F is age-dependent and faster in children than in adults, as seen with other protease inhibitors. Further evaluations are underway in P1020 to establish the optimal dose of ATV/RTV in subjects 91 days to 21 years in the United States and South Africa.

Keywords: pediatrics; atazanavir; pharmacokinetics