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PLoS Med. 2017 Jan 10;14(1):e1002212. doi: 10.1371/journal.pmed.1002212. eCollection 2017 Jan.

Population Pharmacokinetic Properties of Piperaquine in Falciparum Malaria: An Individual Participant Data Meta-Analysis.

Author information

1
WorldWide Antimalarial Resistance Network, Oxford, United Kingdom.
2
Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
3
Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
4
Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa.
5
Department of Drug Evaluation, Australian Army Malaria Institute, Brisbane, Queensland, Australia.
6
Department of Malaria, Military Institute of Hygiene and Epidemiology, Hanoi, Viet Nam.
7
Department of Infectious Diseases, Military Hospital 108, Hanoi, Viet Nam.
8
Institut de Recherche en Sciences de la Santé, Direction Régionale de l'Ouest, Bobo-Dioulasso, Burkina Faso.
9
London School of Hygiene & Tropical Medicine, London, United Kingdom.
10
Kenya Medical Research Institute-Wellcome Trust Research Programme, Kilifi, Kenya.
11
Institute for Tropical Medicine, University of Tübingen, Tübingen, Germany.
12
Joanna Briggs Affiliate Centre for Evidence-Based Health Care, Evidence Synthesis and Translation Unit, Afya Research Africa, Nairobi, Kenya.
13
Global and Tropical Health Division, Menzies School of Health Research and Charles Darwin University, Darwin, Northern Territory, Australia.
14
Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, California, United States of America.
15
Yale School of Public Health and Medicine, New Haven, Connecticut, United States of America.
16
Shoklo Malaria Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Thailand.

Abstract

BACKGROUND:

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.

METHODS AND FINDINGS:

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.

CONCLUSIONS:

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).

PMID:
28072872
PMCID:
PMC5224788
DOI:
10.1371/journal.pmed.1002212
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

KIB and NJW are members of the WHO Technical Expert Group (TEG) on Malaria Chemotherapy. KIB is also a member of the WHO TEG on Drug Resistance and Containment. KIB, NJW, JT and SP are members of the WHO Malaria Chemotherapy sub-group on dosage recommendations. None of the authors declare any other conflict of interest.

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