Population pharmacokinetics of ritonavir as a booster of lopinavir, atazanavir, or darunavir in African children with HIV

Abstract

Ritonavir is important in antiretroviral therapy (ART) because it is used to boost the drug exposure of its fellow protease inhibitors (PIs). While PIs are commonly used in children, ritonavir data in this population are quite scarce. We investigated the population pharmacokinetics of ritonavir given to boost exposures of lopinavir, atazanavir, or darunavir, and co-administered with nucleoside reverse transcriptase inhibitors (NRTIs) in African children, and investigated factors affecting its exposure. We conducted a pharmacokinetic sub-study within the CHAPAS-4 (ISRCTN22964075) trial, which randomized children to two NRTIs with twice-daily lopinavir/ritonavir, once-daily atazanavir/ritonavir, or once-daily darunavir/ritonavir, as second-line ART. Intensive pharmacokinetic blood samples were collected at week 6, and nonlinear mixed-effects modeling was used to identify factors affecting ritonavir pharmacokinetics. In all, 170 children were enrolled in the ritonavir-boosted PI arms of the CHAPAS-4 pharmacokinetic sub-study, with median age 10.6 (range 3.2-15.6) years and weight 26.0 (14.2-64.2) kg. Despite similar dose levels, ritonavir exposure varied widely depending on the companion PI. Compared to children on darunavir/ritonavir, those on atazanavir/ritonavir had 137% (95% CI 107%-190%) higher bioavailability and 20% (95% CI 11.3%-31.3%) faster clearance, while those on lopinavir/ritonavir had 23.4% (95% CI 8.20%-34.4%) lower bioavailability. No effect of NRTIs on ritonavir pharmacokinetics was observed. Ritonavir exposure is higher with atazanavir than with lopinavir or darunavir. These data provide greater insight into the use of ritonavir for boosting PIs in children and help reduce the knowledge gap regarding its exposure in children.

Keywords: NONMEM; pediatric antiretroviral; population pharmacokinetics; protease inhibitors; ritonavir.