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 EMAX-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.
Highlights
Young children are the population most severely affected by Plasmodium falciparum malaria
The pharmacokinetic and pharmacodynamic model was developed based on patients in the PKPD group, and the data from the children in the PD group were used as an external validation of the final pharmacodynamic time-to-event model
Of the 741 apparently healthy children enroled in the study, 42.1% (312) had a positive blood smear for P. falciparum malaria at the beginning of the study, and 21.9% (162) and 36.9% (274) of children acquired at least one new malaria episode during the three rounds of monthly Seasonal malaria chemoprevention (SMC) and the 2 months of follow-up, respectively
Summary
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. Dihydroartemisinin-piperaquine (DHA-PQ) is a potential alternative regimen for SMC in young children in areas where there is resistance to SP3,4,6. The fixed-dose antimalarial drug combination of oral DHA-PQ is an attractive alternative for SMC. It can be administered once daily for three days. Piperaquine is responsible for killing the residual parasites in the body, which remain after three days of dihydroartemisinin and thereby prevents recrudescent malaria. The long terminal elimination half-life of piperaquine provides a long post-treatment prophylactic effect, which lasts at least four weeks if adequate doses are given and fully sensitive parasites are prevalent. Piperaquine is eliminated primarily by metabolism by cytochrome P450 3A4 (CYP3A4)[11,12]
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