Modeling prevention of malaria and selection of drug resistance with different dosing schedules of dihydroartemisinin-piperaquine preventive therapy during pregnancy in Uganda [Clinical Therapeutics]

Dihydroartemisinin-piperaquine (DHA-PQ) is under study for intermittent preventive treatment during pregnancy (IPTp), but it may accelerate selection for drug resistance. Understanding the relationships between piperaquine concentration, prevention of parasitemia, and selection for decreased drug sensitivity can inform control policies and optimization of DHA-PQ dosing. Piperaquine concentrations, measures of parasitemia, and Plasmodium falciparum genotypes associated with decreased aminoquinoline sensitivity in Africa (pfmdr1 86Y, pfcrt 76T) were obtained from pregnant Ugandan women randomized to IPTp with sulfadoxine-pyrimethamine (SP) or DHA-PQ. Joint pharmacokinetic/pharmacodynamic models described relationships between piperaquine concentration and probability of genotypes of interest using nonlinear mixed effects modeling. Increasing piperaquine plasma concentration was associated with a log-linear decrease in risk of parasitemia. Our models predicted that higher median piperaquine concentrations would be required to provide 99% protection against mutant compared to wild type infections (pfmdr1 N86: 9.6 ng/mL, 86Y: 19.6 ng/mL; pfcrt K76: 6.5 ng/mL, 76T: 19.6 ng/mL). Comparing monthly, weekly, and daily dosing, daily low dose DHA-PQ was predicted to result in the fewest infections and the fewest mutant infections per 1,000 pregnancies (predicted mutant infections for pfmdr1 86Y: SP monthly: 607, DHA-PQ monthly: 198, DHA-PQ daily: 1; for pfcrt 76T: SP monthly: 1564, DHA-PQ monthly: 283, DHA-PQ daily: 1). Our models predict that higher piperaquine concentrations are needed to prevent infections with pfmdr1/pfcrt mutant compared to wild type parasites and that, despite selection for mutants by DHA-PQ, the overall burden of mutant infections is lower for IPTp with DHA-PQ than for IPTp with SP.

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