title: Characterization of an in vivo concentration-effect relationship for piperaquine in malaria chemoprevention.
abstract: A randomized, placebo-controlled trial conducted on the northwest border of Thailand compared malaria chemoprevention with monthly or bimonthly standard 3-day treatment regimens of dihydroartemisinin-piperaquine. Healthy adult male subjects (N = 1000) were followed weekly during 9 months of treatment. Using nonlinear mixed-effects modeling, the concentration-effect relationship for the malaria-preventive effect of piperaquine was best characterized with a sigmoidal Emax relationship, where plasma concentrations of 6.7 ng/ml [relative standard error (RSE), 23%] and 20 ng/ml were found to reduce the hazard of acquiring a malaria infection by 50% [that is, median inhibitory concentration (IC50)] and 95% (IC95), respectively. Simulations of monthly dosing, based on the final model and published pharmacokinetic data, suggested that the incidence of malaria infections over 1 year could be reduced by 70% with a recently suggested dosing regimen compared to the current manufacturer's recommendations for small children (8 to 12 kg). This model provides a rational framework for piperaquine dose optimization in different patient groups.
authors.affiliation: Department of Pharmaceutical Biosciences, Uppsala University, Uppsala 751 24, Sweden. martin.bergstrand@farmbio.uu.se.
authors.forename: Martin
authors.initials: M
authors.lastname: Bergstrand
authors.affiliation: Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok 104 00, Thailand. Centre for Tropical Medicine and Global Health, Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX3 7FZ, UK. Shoklo Malaria Research Unit (SMRU), Mae Sod 631 10, Thailand.
authors.forename: François
authors.initials: F
authors.lastname: Nosten
authors.affiliation: Shoklo Malaria Research Unit (SMRU), Mae Sod 631 10, Thailand.
authors.forename: Khin Maung
authors.initials: KM
authors.lastname: Lwin
authors.affiliation: Department of Pharmaceutical Biosciences, Uppsala University, Uppsala 751 24, Sweden.
authors.forename: Mats O
authors.initials: MO
authors.lastname: Karlsson
authors.affiliation: Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok 104 00, Thailand. Centre for Tropical Medicine and Global Health, Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX3 7FZ, UK.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: White
authors.affiliation: Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok 104 00, Thailand. Centre for Tropical Medicine and Global Health, Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX3 7FZ, UK.
authors.forename: Joel
authors.initials: J
authors.lastname: Tarning
mesh_terms: D000962:Antimalarials / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006801:Humans; D008288:Malaria / Q000517:prevention & control*; D008297:Male; D010919:Placebos; D011804:Quinolines / Q000493:pharmacokinetics / Q000627:therapeutic use*; D013785:Thailand; D010879:Piperazines
chemical_list: D000962:Antimalarials; D010919:Placebos; D011804:Quinolines; C034759:piperaquine; D010879:Piperazines