Identifying an optimal dihydroartemisinin-piperaquine dosing regimen for malaria prevention in young Ugandan children

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.

Conflict of interest statement

The authors declare no competing interests.

© 2021. The Author(s).

Figures

Fig. 1. Summary of trial interventions and sampling for piperaquine concentrations.

Blue dots indicate dihydroartemisinin-piperaquine (DP) courses dispensed, and dashes indicate episodes when a placebo was given. The red dots indicate sparse pharmacokinetic (PK) sampling for piperaquine concentrations (all participants contributed data) and red lines indicate typical pharmacokinetic profiles. Intensive sampling, in orange dots, occurred at 32 and 104 weeks (22 individuals in every 12 weeks and 10 in the every 4 weeks arm).

Fig. 2. Study participant follow-up and malaria outcomes in the clinical trial.

DP indicates dihydroartemisinin-piperaquine.

Fig. 3. Raw pharmacokinetic data.

A Piperaquine (PPQ) concentration from intensive sampling after the third daily dihydroartemisinin-piperaquine (DP) dose (day 2) for 32 children at 32 and 104 weeks of age. B PPQ concentrations from sparse sampling obtained from 280 children at 28-days intervals. Boxes indicate PPQ levels for 25% (minima), 50% (center), and 75% (maxima) of the population.

Fig. 4. Malaria outcomes data.

A Malaria incidence per person year, stratified by dihydroartemisinin-piperaquine (DP) regimen. The lines indicate malaria incidence for the DP every 12 weeks (n = 184) (blue) and every 4 weeks (n = 96) (red) arms. Gray bands indicate periods of indoor residual spraying, and horizontal bars indicate times when participants received DP (pink) or were monitored off DP (purple). As study enrollment occurred over several months, there was a period where part of the cohort was on DP and others had completed the intervention (overlap between pink and purple bars). Time to malaria after receiving DP in the every 12-week arm B and the every 4-week arm C stratified by malaria transmission period. The low transmission periods are combined and the high transmission periods are shown separately.

Fig. 5. Relationship between piperaquine (PPQ) concentration and protective efficacy.

A Measured PPQ concentrations by days after dihydroartemisinin-piperaquine (DP) and at time of malaria diagnosis (n = 280 children). Points indicate observed data, boxes indicate PPQ levels for 25% (minima), 50% (center), and 75% (maxima) of the population, and vertical bars represent PPQ levels for 95% of the population. B Relationship between PPQ concentration and protective efficacy. The solid line indicates the median estimate from the pharmacokinetic/pharmacodynamic model, and the shaded areas the 95% confidence interval. The indicated concentration (15.4 ng/mL) reduced the hazard of incident malaria by 95%.

Fig. 6. Simulation results stratified by weight for age z-score (WAZ).

A Predicted piperaquine (PPQ) trough concentrations for simulated dihydroartemisinin-piperaquine (DP) regimens, stratified by nutritional status. Data are derived from 1000 simulations of 856 children <2 years of age. The red line indicates the 15.4 ng/mL PPQ target. Points indicate observed data, boxes indicate PPQ levels for 25% (minima), 50% (center), and 75% (maxima) of the population, and vertical bars represent PPQ levels for 95% of the population. B Predicted malaria incidence by DP regimen with increasing baseline malaria transmission, stratified by nutritional status and adherence level (1/3 adherence indicates bioavailability observed for non-direct observed therapy in the study, 2/3 adherence indicates a bioavailability midpoint between the directly and non-directly observed population, and full adherence indicates the bioavailability observed in the directly observed therapy group). Data are derived from 10,000 simulations of 856 children <2 years of age. C Predicted peak PPQ concentrations by DP regimen, assuming full adherence. Data are derived from 1000 simulations of 280 children <2 years of age. Points indicate observed data, boxes indicate PPQ levels for 25% (minima), 50% (center), and 75% (maxima) of the population, and vertical bars represent PPQ levels for 95% of the population. In text is the median and 2.5–97.5% range of predicted population values for peak PPQ concentrations during chemoprevention. Age-based dosing indicates daily PPQ doses as follows: <6 months = 160 mg; 6–<18 mo = 240 mg; 18–26 mo = 320 mg.