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

## TL;DR

This study examines how ritonavir's drug levels vary in African children with HIV when used to boost different antiretroviral drugs.

## Contribution

The study provides new population pharmacokinetic data on ritonavir in African children, comparing its behavior when boosting different protease inhibitors.

## Key findings

- Ritonavir exposure varies significantly depending on the protease inhibitor it is boosting.
- Children on atazanavir/ritonavir had higher bioavailability and faster clearance compared to those on darunavir/ritonavir.
- Lopinavir/ritonavir showed lower bioavailability compared to atazanavir/ritonavir.

## 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.