Optimal dosing of dihydroartemisinin-piperaquine for seasonal malaria chemoprevention in young children

Abstract

Young children are the population most severely affected by Plasmodium falciparum malaria. Seasonal malaria chemoprevention (SMC) with amodiaquine and sulfadoxine-pyrimethamine provides substantial benefit to this vulnerable population, but resistance to the drugs will develop. Here, we evaluate the use of dihydroartemisinin-piperaquine as an alternative regimen in 179 children (aged 2.33-58.1 months). Allometrically scaled body weight on pharmacokinetic parameters of piperaquine result in lower drug exposures in small children after a standard mg per kg dosage. A covariate-free sigmoidal E_MAX-model describes the interval to malaria re-infections satisfactorily. Population-based simulations suggest that small children would benefit from a higher dosage according to the WHO 2015 guideline. Increasing the dihydroartemisinin-piperaquine dosage and extending the dose schedule to four monthly doses result in a predicted relative reduction in malaria incidence of up to 58% during the high transmission season. The higher and extended dosing schedule to cover the high transmission period for SMC could improve the preventive efficacy substantially.

Fig. 1

Visual predictive checks of the final population pharmacokinetic and pharmacodynamic model of piperaquine. a The final population pharmacokinetic model, b the interval-censoring time-to-event model of the internal data, and c the final pharmacodynamic model predicting the external data. Open circles represent observed capillary plasma piperaquine concentrations and open triangles represent observed venous plasma concentrations. A solid line represents the median observed plasma concentrations and dashed lines represent the 5^th and 95^th percentiles of the observed plasma concentrations. Shaded areas represent the predicted 95% confidence intervals of each percentile. Solid lines in panel (b) and (c) represent observed Kaplan–Meier survival plots. Shaded areas represent the 95% prediction intervals

Fig. 2

Simulated venous piperaquine concentrations. a Day-7 piperaquine concentrations and b peak piperaquine concentrations after different dosing regimens, stratified by body weight. The box-whisker plots represent the median with inter-quartile range and the 95% prediction interval of 1000 simulated individuals per body weight. The horizontal dashed line represents the previously defined 30 ng mL^-1 cut-off concentration at day 7 associated with therapeutic success

Fig. 3

Simulation of the expected pharmacodynamic outcome. a remaining malaria-free after a single treatment regimen, b remaining malaria-free after three rounds of monthly dose regimens (day 0, 30, and 60), and c remaining malaria-free after four rounds of monthly dose regimens (day 0, 30, 60, and 90). Red lines represent the standard WHO 2010 dosing regimen^, and black lines the increased dosing regimens according to the revised WHO 2015 recommendation in children (4–20 kg; n = 200 individuals per body weight, 100 replications). Solid lines represent the predicted median survival estimate of the Kaplan–Meier plot and shaded areas represent the 95% prediction intervals. Upward red arrows represent the time of DHA-PQ administrations

Fig. 4

Comparisons of the expected pharmacodynamic outcomes. a Children (4–20 kg) remaining malaria-free after a single treatment regimen by day 60, b children (4–20 kg) remaining malaria-free after three rounds of a monthly dose regimen by day 120, c children (4–20 kg) remaining malaria-free after three rounds of a monthly dose regimen by day 90, d children (4–20 kg) remaining malaria-free after four rounds of a monthly dose regimen by day 120. Red box-whisker plots represent the standard WHO 2010 dosing regimen^, and blue box-whisker plots represent the increased dosing regimens according to the revised WHO 2015 recommendation, stratified by body weight. The simulations are based on 200 individuals per body weight for 100 replications. The box-whisker plots represent the median with inter-quartile range and the 95% prediction interval. Right panels represent the proportions of children remaining malaria-free at the end time point; the red filled density plots represent the standard WHO 2010 dosing regimen and the blue filled density plots represent the revised WHO 2015 dosing regimen