Population pharmacokinetic properties of piperaquine in falciparum malaria: An individual participant data meta-analysis
Richard M. Hoglund (1,2,3), Lesley Workman (1,4), Michael D. Edstein (5), Nguyen Xuan Thanh (6), Nguyen Ngoc Quang (7), Issaka Zongo (8,9), Jean Bosco Ouedraogo (8), Steffen Borrmann (10,11), Leah Mwai (10,12), Christian Nsanzabana (1,3), Ric N. Price (1,3,13), Prabin Dahal (1,3), Nancy C. Sambol (14), Sunil Parikh (15), Francois Nosten (3,16), Elizabeth A. Ashley (16), Aung Pyae Phyo (16), Khin Maung Lwin (16), Rose McGready (3,16), Nicholas P. J. Day (2,3), Philippe J. Guerin (1,3), Nicholas J. White (2,3), Karen I. Barnes (1,4), Joel Tarning (1,2,3)
(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 Sante, Direction Regionale 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 Tubingen, Tubingen, 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
Objectives: Dihydroartemisinin-piperaquine is one of the five first-line therapies currently recommended by the World Health Organization for malaria. Previous studies [1,2] suggest that young children (< 5 year) with malaria are under-dosed. This study [3] utilised pooled individual level data and a population-based pharmacokinetic approach to optimise the antimalarial treatment regimen for piperaquine.
Methods: Published pharmacokinetic studies were identified through a systematic review of articles published between 1960 and 2013. Individual plasma piperaquine concentration-time data from 11 clinical studies (8,776 samples from 728 individuals) were collated and standardised by the WorldWide Antimalarial Resistance Network. Data were pooled and analysed using nonlinear mixed-effects modelling (NONMEM v.7).
Results: Piperaquine pharmacokinetics were described successfully by a three-compartment disposition model with flexible absorption. Body weight was incorporated as an allometric function, resulting in lower exposures in small children (< 25 kg) compared to larger children and adults (> 25 kg) after administration of the manufacturers' currently recommended dose regimens. The final model identified a mean (95% CI) increase of 23.7% (15.8%±32.5%) in piperaquine bioavailability between each 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) year of age. Simulations were used to construct an evidence-based optimised dose regimen that would provide piperaquine exposures across all ages comparable to the exposure currently seen in a typical adult with standard treatment, without exceeding the maximum concentration observed with the manufacturers' recommended regimen.
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).
References:
[1] J. Tarning, et al. Population pharmacokinetics and pharmacodynamics of piperaquine in children with uncomplicated falciparum malaria. Clinical Pharmacology & Therapeutics. 2012 Mar;91(3):497-505.
[2] R. Price, et al. The effect of dosing regimens on the antimalarial efficacy of dihydroartemisinin piperaquine: a pooled analysis of individual patient data. PLoS Medicine. 2013 Dec;10(12):e1001564.
[3] R.M. Hoglund, et al. Population Pharmacokinetic Properties of Piperaquine in Falciparum Malaria: an Individual Participant Data-level Meta-analysis. PLoS Medicine. 2017 Jan 10;14(1):e1002212.