Paediatric dose finding atazanavir and atazanavir/ritonavir

Jennifer Kiser and colleagues reported findings from PACTG 1020, 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) in HIV-positive children in combination with two nucleosides.

ART-naïve and -experienced children with viral load > 5000 copies/mL and ATV phenotypic susceptibility (< 10-fold wild type IC50) were eligible for this study.

There are 8 study groups in PACTG 1020: groups 1 to 4 evaluating unboosted and in groups 5 to 8 boosted ATV. This poster reported preliminary PK data from 23 children in groups 5-8 receive RTV boosted ATV at a dose of 310mg/m².

Intensive PK studies were performed on day 7 and at week 56, plus 14 days after dose adjustment. A new ATV dose is calculated for children with: an AUC <30µg*hr/mL or AUC >90µg*hr/mL, increases of 25% in weight.

The authors reported week 1 pharmacokinetic results for 23 children ages 0.3-19.6 years. Overall median AUC and oral clearance (CL/F) were 60.8µg*hr/mL and 4.7L/hr/m² respectively.

In the youngest group (group 5, median age 1.0 [range 0.3-1.3] years, n = 6), median AUC and oral clearance (CL/F) were 53.6 (range 7.3-110) mcg•hr/mL and 8.1 (range 2.5-36) L/hr/m² in children receiving powder at a dose of 125 (range 50-150)mg /298 (range182-367)mg/m².

In older children receiving powder (group 6, median age 4.1 [range 2.6-12] years, n = 7), the median AUC and CL/F were 50.3 mcg•hr/mL and 6.2 L/hr/m² at a dose of 200 (range 150-500) mg/312 (range 268-327) mg/m². Older children receiving capsules (group 7, median age 10.5 [range 8.7-11.5], n=5) the median AUC and CL/F were 73.8 (range 60-134.2) mcg•hr/mL and 4.2 (range 2.2-4.7) L/hr/m² at a dose of 400 (range 300-500) mg/286 (range 274-349) mg/m².

In the oldest group of children receiving capsules (group 8, median age 17.7 [range 13.1-19.6], n=5) the median AUC and CL/F were 62.4 (range 51.5-84.7) mcg•hr/mL and 4.5 (range 3.4-6.0) L/hr/m2 at a dose of 500 (range 400-600) mg/286 (range 281-311) mg/m².

The authors concluded: “The median ATV AUC and CL/F in adults receiving ATV/RTV 300/100mg once daily are 53.8 µg•hr/mL and 3.2 L/hr/m² respectively. Thus ATV CL/F is age-dependent and faster in children than in adults, as seen with other protease inhibitors.

“As expected, the addition of RTV decreases the clearance and increases the AUC of ATV in children.”

These data are preliminary and the optimal dose of ATV/RTV has not yet been established. The authors added: “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.”