Population pharmacokinetics of ritonavir-boosted atazanavir in subsequent-line treatment in African children with HIV

Ritonavir-boosted atazanavir (atazanavir/r) is an effective once-daily option for pediatric subsequent-line antiretroviral therapy when used with two nucleoside reverse transcriptase inhibitors (NRTIs). Tuberculosis co-treatment complicates its use because rifampicin markedly induces atazanavir/r clearance. Although twice-daily atazanavir/r can overcome this interaction in adults, data in children are lacking. We aimed to characterize atazanavir population pharmacokinetics in children with HIV and simulate the effect of rifampicin co-treatment. Atazanavir concentration-time data in African children with HIV from CHAPAS-4 (ISRCTN22964075) and VirTUAL (NCT03923231) were analyzed by nonlinear mixed-effect modeling. We investigated the effect of weight, age, atazanavir formulation, ritonavir dose, and NRTI backbone (tenofovir alafenamide [TAF]-emtricitabine, abacavir-lamivudine, or zidovudine-lamivudine). Simulations were performed across weight bands to evaluate atazanavir/r exposures under standard conditions and, using adult-derived induction effects, predict exposures and possible dosing regimens during rifampicin co-treatment. Seventy children were included, with a median (range) age of 10.9 (3.2-17.7) years and weight of 29 (15-85) kg. A two-compartment model with sequential zero- and first-order absorption best described atazanavir disposition. The estimated typical value of atazanavir clearance was 4.8 L/h for a 27-kg individual. Atazanavir pharmacokinetics in children were unaffected by the NRTI backbone. Once-daily atazanavir/r with current dosing guidelines achieved adequate exposures across weight bands. When simulating pharmacokinetics during rifampicin co-treatment, twice-daily atazanavir/r is expected to restore exposures to levels comparable to once-daily dosing without rifampicin. These findings provide a framework for future clinical evaluation in children with HIV and tuberculosis.