Abstract
Intermittent preventive treatment (IPT) with dihydroartemisinin-piperaquine (DP) is highly protective against malaria in children, but is not standard in malaria-endemic countries. Optimal DP dosing regimens will maximize efficacy and reduce toxicity and resistance selection. We analyze piperaquine (PPQ) concentrations (n = 4573), malaria incidence data (n = 326), and P. falciparum drug resistance markers from a trial of children randomized to IPT with DP every 12 weeks (n = 184) or every 4 weeks (n = 96) from 2 to 24 months of age (NCT02163447). We use nonlinear mixed effects modeling to establish malaria protective PPQ levels and risk factors for suboptimal protection. Compared to DP every 12 weeks, DP every 4 weeks is associated with 95% protective efficacy (95% CI: 84–99%). A PPQ level of 15.4 ng/mL reduces the malaria hazard by 95%. Malnutrition reduces PPQ exposure. In simulations, we show that DP every 4 weeks is optimal across a range of transmission intensities, and age-based dosing improves malaria protection in young or malnourished children.
Highlights
Intermittent preventive treatment (IPT) with dihydroartemisinin-piperaquine (DP) is highly protective against malaria in children, but is not standard in malaria-endemic countries
Participant characteristics were similar between the two IPT arms, with the exception that none of the children who received DP every 4 weeks were born to mothers who received IPT with SP during pregnancy as per the trial protocol (Table 1)
We report a PK/PD analysis based on the largest longitudinal clinical trial of IPT with DP in young children, including longitudinal pharmacokinetic, incident malaria, electrocardiographic, and drug sensitivity data
Summary
Intermittent preventive treatment (IPT) with dihydroartemisinin-piperaquine (DP) is highly protective against malaria in children, but is not standard in malaria-endemic countries. We analyze piperaquine (PPQ) concentrations (n = 4573), malaria incidence data (n = 326), and P. falciparum drug resistance markers from a trial of children randomized to IPT with DP every 12 weeks (n = 184) or every 4 weeks (n = 96) from 2 to 24 months of age (NCT02163447). To gain insights into optimal DP regimens for IPT in young Ugandan children, we leveraged data from a randomized controlled trial and used pharmacokinetic/pharmacodynamic (PK/PD) modeling to describe the pharmacokinetics (PK) of PPQ and characterize relationships between PPQ exposure and risks of malaria, toxicity, and selection for markers of aminoquinoline resistance. We conducted simulations to quantify how optimized DP dosing regimens between 2 and 24 months of age would decrease malaria incidence, risk of QTc prolongation, and selection for P. falciparum markers of decreased antimalarial drug sensitivity
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