title: Population Pharmacokinetic Properties of Piperaquine in Falciparum Malaria: An Individual Participant Data Meta-Analysis.
abstract: Artemisinin-based combination therapies (ACTs) are the mainstay of the current treatment of uncomplicated Plasmodium 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 (<5 y) with malaria are under-dosed. This study utilised a population-based pharmacokinetic approach to optimise the antimalarial treatment regimen for piperaquine.
  
  
  
  Published pharmacokinetic studies on piperaquine were identified through a systematic literature review of articles published between 1 January 1960 and 15 February 2013. Individual plasma piperaquine concentration-time data from 11 clinical studies (8,776 samples from 728 individuals) in adults and children with uncomplicated malaria and 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. Body weight influenced clearance and volume parameters significantly, resulting in lower piperaquine exposures in small children (<25 kg) compared to larger children and adults (≥25 kg) after administration of the manufacturers' currently recommended dose regimens. Simulated median (interquartile range) day 7 plasma concentration was 29.4 (19.3-44.3) ng/ml in small children compared to 38.1 (25.8-56.3) ng/ml in larger children and adults, with the recommended dose regimen. 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 function in very young children, resulting in 50% maturation at 0.575 (0.413-0.711) y of age. An evidence-based optimised dose regimen was constructed that would provide piperaquine exposures across all ages comparable to the exposure currently seen in a typical adult with standard treatment, 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.
  
  
  
  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 small children with malaria. Use of this dose regimen is expected to 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).
authors.affiliation: WorldWide Antimalarial Resistance Network, Oxford, United Kingdom.|Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.|Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Hoglund
authors.affiliation: WorldWide Antimalarial Resistance Network, Oxford, United Kingdom.|Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa.
authors.forename: Lesley
authors.identifier: 0000-0002-3433-6106
authors.initials: L
authors.lastname: Workman
authors.affiliation: Department of Drug Evaluation, Australian Army Malaria Institute, Brisbane, Queensland, Australia.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Edstein
authors.affiliation: Department of Malaria, Military Institute of Hygiene and Epidemiology, Hanoi, Viet Nam.
authors.forename: Nguyen Xuan
authors.initials: NX
authors.lastname: Thanh
authors.affiliation: Department of Infectious Diseases, Military Hospital 108, Hanoi, Viet Nam.
authors.forename: Nguyen Ngoc
authors.identifier: 0000-0001-8703-0891
authors.initials: NN
authors.lastname: Quang
authors.affiliation: Institut de Recherche en Sciences de la Santé, Direction Régionale de l'Ouest, Bobo-Dioulasso, Burkina Faso.|London School of Hygiene & Tropical Medicine, London, United Kingdom.
authors.forename: Issaka
authors.initials: I
authors.lastname: Zongo
authors.affiliation: Institut de Recherche en Sciences de la Santé, Direction Régionale de l'Ouest, Bobo-Dioulasso, Burkina Faso.
authors.forename: Jean Bosco
authors.initials: JB
authors.lastname: Ouedraogo
authors.affiliation: Kenya Medical Research Institute-Wellcome Trust Research Programme, Kilifi, Kenya.|Institute for Tropical Medicine, University of Tübingen, Tübingen, Germany.
authors.forename: Steffen
authors.initials: S
authors.lastname: Borrmann
authors.affiliation: Kenya Medical Research Institute-Wellcome Trust Research Programme, Kilifi, Kenya.|Joanna Briggs Affiliate Centre for Evidence-Based Health Care, Evidence Synthesis and Translation Unit, Afya Research Africa, Nairobi, Kenya.
authors.forename: Leah
authors.initials: L
authors.lastname: Mwai
authors.affiliation: WorldWide Antimalarial Resistance Network, Oxford, United Kingdom.|Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Christian
authors.initials: C
authors.lastname: Nsanzabana
authors.affiliation: WorldWide Antimalarial Resistance Network, Oxford, United Kingdom.|Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.|Global and Tropical Health Division, Menzies School of Health Research and Charles Darwin University, Darwin, Northern Territory, Australia.
authors.forename: Ric N
authors.identifier: 0000-0003-2000-2874
authors.initials: RN
authors.lastname: Price
authors.affiliation: WorldWide Antimalarial Resistance Network, Oxford, United Kingdom.|Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Prabin
authors.identifier: 0000-0002-2158-846X
authors.initials: P
authors.lastname: Dahal
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Nancy C
authors.identifier: 0000-0003-1333-4838
authors.initials: NC
authors.lastname: Sambol
authors.affiliation: Yale School of Public Health and Medicine, New Haven, Connecticut, United States of America.
authors.forename: Sunil
authors.initials: S
authors.lastname: Parikh
authors.affiliation: Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.|Shoklo Malaria Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Thailand.
authors.forename: Francois
authors.identifier: 0000-0002-7951-0745
authors.initials: F
authors.lastname: Nosten
authors.affiliation: Shoklo Malaria Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Thailand.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Ashley
authors.affiliation: Shoklo Malaria Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Thailand.
authors.forename: Aung Pyae
authors.identifier: 0000-0002-0383-9624
authors.initials: AP
authors.lastname: Phyo
authors.affiliation: Shoklo Malaria Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Thailand.
authors.forename: Khin Maung
authors.initials: KM
authors.lastname: Lwin
authors.affiliation: Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.|Shoklo Malaria Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Thailand.
authors.forename: Rose
authors.identifier: 0000-0003-1621-3257
authors.initials: R
authors.lastname: McGready
authors.affiliation: Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.|Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Nicholas P J
authors.initials: NP
authors.lastname: Day
authors.affiliation: WorldWide Antimalarial Resistance Network, Oxford, United Kingdom.|Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Philippe J
authors.identifier: 0000-0002-6008-2963
authors.initials: PJ
authors.lastname: Guerin
authors.affiliation: Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.|Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Nicholas J
authors.identifier: 0000-0002-1897-1978
authors.initials: NJ
authors.lastname: White
authors.affiliation: WorldWide Antimalarial Resistance Network, Oxford, United Kingdom.|Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa.
authors.forename: Karen I
authors.initials: KI
authors.lastname: Barnes
authors.affiliation: WorldWide Antimalarial Resistance Network, Oxford, United Kingdom.|Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.|Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Joel
authors.identifier: 0000-0003-4566-4030
authors.initials: J
authors.lastname: Tarning
mesh_terms: D000962:Antimalarials / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy*; D010963:Plasmodium falciparum / Q000187:drug effects; D011804:Quinolines / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use*; D010879:Piperazines
chemical_list: D000962:Antimalarials; D011804:Quinolines; C034759:piperaquine; D010879:Piperazines