Pharmacokinetics of piperaquine co administered with ritonavir boosted lopinavir antiretroviral therapy in Ugandan children without malaria

Abstract

Background: Dihydroartemisinin–piperaquine (DHA–PQ) is widely used for malaria treatment and prevention in children, including those living with HIV. Piperaquine (PQ) exposure, which determines both efficacy and safety, may be altered by drug–drug interactions with antiretroviral therapy (ART), particularly ritonavir-boosted lopinavir (LPV/r) leading to safety concerns. However, there is limited information on the PQ and LPV/r interaction in HIV infected children. Objective: This study evaluated PQ pharmacokinetics (PK) in HIV-uninfected Ugandan children and HIV-infected children receiving LPV/r-based ART. Methods: A retrospective analysis utilized data from a prospective, open-label study of DHA–PQ in children with and without HIV in Uganda. Pharmacokinetic parameters were assessed following a single dose in HIV-uninfected children and after a 3-dose regimen in both HIV-uninfected children and HIV-infected children on LPV/r-based ART. PQ concentrations were analyzed to estimate Cmax, area under the concentration–time curve (AUC), and terminal half-life (t½). Results: Among the HIV-uninfected children who received a single dose of DHA-PQ, the median age was 5.9 years (IQR: 4.9–7.1), and the majority were female (65%). The the median body weight and height were 20.6 kg (IQR: 18.1–23.4) and 115.7 cm (IQR: 108.7–123.2), respectively. The geometric mean AUC0-24hr was 1687 hr·ng/mL (95% CI: 1279.–2226), geometric mean Cmax was 197.9 ng/mL (95% CI: 141–278). The median Tmax was 2.1 hours (IQR: 2–3). Among the HIV-uninfected children who received three doses of DHA-PQ, the median age was 7.4 years (IQR: 6.0–8.7 years), weight was 23.6 kg (IQR: 21.4–27.9 kg), the geometric mean PQ Cmax was 218 ng/mL (90% CI: 175–272 ng/mL) and AUC0–day 42 was 14.6 hr·µg/mL (90% CI: 12.7–16.7 hr·µg/mL), with a terminal t½ of 435 hours (90% CI: 377–502 hours). In contrast, HIV-infected children on LPV/r-based ART, the median age was 7.1 years (IQR: 6.0–8.7 years), weight was 19.0 kg (IQR: 17.4–22.5 kg), and exhibited markedly higher exposures with a Cmax of 491 ng/mL (90% CI: 397–608 ng/mL) and AUC0–day 42 of 49700 hr·ng/mL (90% CI: 41700–59200 hr·ng/mL), representing a 3.3-fold increase compared to uninfected controls (GMR 3.40; p < 0.0001). The terminal t½ was slightly shorter at 414 hours (90% CI: 364–471 hours). Statistical analysis showed a highly significant increament in PQ exposure with a GMR of 3.40 (p < 0.0001). The present findings indicates significant differences in PQ pharmacokinetics among HIV-infected children on LPV/r and HIV-uninfected controls. Conclusions: LPV/r-based ART significantly increased PQ exposure in HIV-infected children, highlighting a strong drug–drug interaction with clinical implications for malaria chemoprevention and treatment. In contrast, PQ pharmacokinetics in HIV-uninfected children were consistent with standard dosing guidelines. These findings underscore the need for adjust dosing strategies to a lower dose and perform therapeutic monitoring to optimize malaria prevention and treatment in HIV-infected pediatric population