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.

Fig 1

Visual predictive check stratified by boosted protease inhibitor. The solid and dashed lines represent the 5th, 50th, and 95th percentiles of the observed data, while the shaded areas represent the model-predicted 95% confidence intervals for the same percentiles. The circles are the observed concentrations. The outliers in the darunavir arm had taken the previous dose at night while everyone else took it in the morning.

Fig 2

Covariate effects plot showing the relative differences in ritonavir (RTV) area under the curve (AUC_{0–24 h}) among different covariates. The reference child has a weight of 26 kg and is on 100 mg ritonavir and 800 mg darunavir. All children in different weight categories are on 100 mg ritonavir. Abbreviations: BSV; between subject variability (50% and 90% indicate the percentage of patients whose AUC_0-24h falls within the range defined by the red lines), PI, protease inhibitor; NRTI, nucleoside reverse transcriptase inhibitors; REF, reference; DRV, darunavir; LPV, lopinavir; ATV, atazanavir.