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Background: Artemisinin-based combination therapies (ACTs) are the mainstay of the current treatment of uncomplicated P.falciparum malaria, but ACT resistance is spreading across Southeast Asia. Dihydroartemisinin-piperaquine is one of the five ACTs currently recommended by the World Health Organization. Previous studies suggest that young children (Methods and Findings: Published pharmacokinetic studies on piperaquine were identified through a systematic literature review of articles published between January 1960 and February 2013. Individual plasma piperaquine concentration-time data from eleven clinical studies (8,776 samples from 728 individuals) in both adults and children with uncomplicated malaria or healthy volunteers were collated and standardised by the WorldWide Antimalarial Resistance Network. Data were pooled and analysed using nonlinear mixed-effects modelling. Piperaquine pharmacokinetics were described successfully by a three-compartment disposition model with flexible absorption. Bodyweight influenced clearance and volume parameters significantly, resulting in lower piperaquine exposures in young children compared to older children and adults after administration of the manufacturers’ currently recommended dose regimens. Simulated median (interquartile range) day 7 plasma concentrations were 29.4 (19.3-44.3) ng/mL in young children (25 kg), at recommended dose regimens. The final model identified a mean (95% confidence interval) increase of 23.7% (15.8%-32.5%) in piperaquine bioavailability between each piperaquine dose occasion. The model also described an enzyme maturation in very young children, resulting in 50% maturation at 0.575 (0.413-0.711) years of age. An evidence-based optimised dose regimen was constructed which provided equivalent piperaquine exposures across all ages without exceeding the concentration range observed with the manufacturers recommended regimen. Limited data were available in infants and pregnant women with malaria as well as in healthy individuals. Conclusion: The derived population pharmacokinetic model was used to develop a revised dose regimen of dihydroartemisinin-piperaquine that is expected to provide equivalent piperaquine exposures safely in all patients, including in young children with malaria. This should prolong the useful therapeutic life of dihydroartemisinin-piperaquine by increasing cure rates and thereby slowing resistance development. This work was part of the evidence that informed the World Health Organization Technical Guidelines Development group in the development of the recently published treatment guidelines (2015).

Background: Artemisinin-based combination therapies (ACTs) are the mainstay of the current treatment of uncomplicated P.falciparum malaria, but ACT resistance is spreading across Southeast Asia. Dihydroartemisinin-piperaquine is one of the five ACTs currently recommended by the World Health Organization. Previous studies suggest that young children (Methods and Findings: Published pharmacokinetic studies on piperaquine were identified through a systematic literature review of articles published between January 1960 and February 2013. Individual plasma piperaquine concentration-time data from eleven clinical studies (8,776 samples from 728 individuals) in both adults and children with uncomplicated malaria or healthy volunteers were collated and standardised by the WorldWide Antimalarial Resistance Network. Data were pooled and analysed using nonlinear mixed-effects modelling. Piperaquine pharmacokinetics were described successfully by a three-compartment disposition model with flexible absorption. Bodyweight influenced clearance and volume parameters significantly, resulting in lower piperaquine exposures in young children compared to older children and adults after administration of the manufacturers’ currently recommended dose regimens. Simulated median (interquartile range) day 7 plasma concentrations were 29.4 (19.3-44.3) ng/mL in young children (25 kg), at recommended dose regimens. The final model identified a mean (95% confidence interval) increase of 23.7% (15.8%-32.5%) in piperaquine bioavailability between each piperaquine dose occasion. The model also described an enzyme maturation in very young children, resulting in 50% maturation at 0.575 (0.413-0.711) years of age. An evidence-based optimised dose regimen was constructed which provided equivalent piperaquine exposures across all ages without exceeding the concentration range observed with the manufacturers recommended regimen. Limited data were available in infants and pregnant women with malaria as well as in healthy individuals. Conclusion: The derived population pharmacokinetic model was used to develop a revised dose regimen of dihydroartemisinin-piperaquine that is expected to provide equivalent piperaquine exposures safely in all patients, including in young children with malaria. This should prolong the useful therapeutic life of dihydroartemisinin-piperaquine by increasing cure rates and thereby slowing resistance development. This work was part of the evidence that informed the World Health Organization Technical Guidelines Development group in the development of the recently published treatment guidelines (2015).

BACKGROUND: Drug resistance remains a chief concern for malaria control. In order to determine the genetic markers of drug resistant parasites, we tested the genome-wide associations (GWA) of sequence-based genotypes from 35 Kenyan P. falciparum parasites with the activities of 22 antimalarial drugs. METHODS AND PRINCIPAL FINDINGS: Parasites isolated from children with acute febrile malaria were adapted to culture, and sensitivity was determined by in vitro growth in the presence of anti-malarial drugs. Parasites were genotyped using whole genome sequencing techniques. Associations between 6250 single nucleotide polymorphisms (SNPs) and resistance to individual anti-malarial agents were determined, with false discovery rate adjustment for multiple hypothesis testing. We identified expected associations in the pfcrt region with chloroquine (CQ) activity, and other novel loci associated with amodiaquine, quinazoline, and quinine activities. Signals for CQ and primaquine (PQ) overlap in and around pfcrt, and interestingly the phenotypes are inversely related for these two drugs. We catalog the variation in dhfr, dhps, mdr1, nhe, and crt, including novel SNPs, and confirm the presence of a dhfr-164L quadruple mutant in coastal Kenya. Mutations implicated in sulfadoxine-pyrimethamine resistance are at or near fixation in this sample set. CONCLUSIONS/SIGNIFICANCE: Sequence-based GWA studies are powerful tools for phenotypic association tests. Using this approach on falciparum parasites from coastal Kenya we identified known and previously unreported genes associated with phenotypic resistance to anti-malarial drugs, and observe in high-resolution haplotype visualizations a possible signature of an inverse selective relationship between CQ and PQ.