Small children and pregnant women may be underdosed in current malaria regimen

Current recommended dosing regimens for the most widely used treatment for uncomplicated Plasmodium falciparum malaria may be sub-optimal for the most vulnerable populations of patients, according to a study published this week in PLOS Medicine, led by Prof Joel Tarning of the WorldWide Antimalarial Resistance Network and the Mahidol Oxford Tropical Medicine Research Network (MORU).

Artemether-lumefantrine is the most widely used treatment for uncomplicated Plasmodium falciparum malaria, but lower cure rates have been reported in children below 5 years of age and pregnant women. Pharmacokinetic-pharmacodynamic trials are generally small, and individual studies typically do not enrol enough young children or pregnant women to assess properly the pharmacological properties in these specific groups. To respond to this challenge, a team of researchers from multiple institutions conducted a systematic review and meta-analysis using individual patient data from 26 clinical studies published between 1990 and 2013.

The researchers pooled relevant individual data on lumefantrine blood level measurements, clinical covariates, and outcome data from 4,122 patients who received artemether-lumefantrine, and developed a pharmacological model to understand how body weight, pregnancy, and baseline parasite density influence drug levels in patients. The results suggest that that lumefantrine concentrations 7 days after starting standard 3-day treatment were 24% and 13% lower in children weighing <15 kg and 15-25 kg, respectively, and 20% lower in pregnant women compared with older children and non-pregnant adults.

The reseachers used their model to evaluate alternative dosing regimens and determined that a longer 5-day regimen for small children and pregnant women, beyond their first trimester, appears most favourable from a pharmacological perspective. The study suggests that the proposed revised artemether-lumefantrine dosing regimen should provide a number of positive effects, including safe and effective lumefantrine exposures and exposure of the parasite to artemether for an additional asexual life cycle.

The authors note that these predictions based on blood levels of one drug in the combination (lumefantrine) and lack of data on the levels of the other drug (artemether) prevented their ability to predict parasite killing rates and recrudescent infections, and that any new dosing regimens will need to be evaluated in prospective clinical studies to confirm safety and superiority to current regimens.

The study lead author Prof Tarning concludes, "This proposed revised artemether-lumefantrine regimen will hopefully improve the treatment of malaria in vulnerable patient groups and delay drug resistance development, a serious concern in many areas of South-East Asia and beyond, and therefore prolong the useful therapeutic life of this life-saving antimalarial combination treatment."

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Research Article

Funding:

The Mahidol-Oxford Tropical Medicine Research Unit is partly funded by the Wellcome Trust of Great Britan (106698/Z/14/Z). The WorldWide Antimalarial Resistance Network is funded by a Bill & Melinda Gates Foundation grant (OPP1181807 started October 2017 and OPP1099191 ended in Sept 2017). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing Interests:

I have read the journal's policy and the authors of this manuscript have the following competing interests: 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. GL is employee of Novartis, the manufacturer of the drug that is the subject of this publication, and has been closely involved in the development program of this drug. EAA and NJW are members of the Editorial Board of PLOS Medicine. None of the authors declare any other conflict of interest.

Citation:

Kloprogge F, Workman L, Borrmann S, Tékété M, Lefèvre G, Hamed K, et al. (2018) Artemether-lumefantrine dosing for malaria treatment in young children and pregnant women: A pharmacokinetic-pharmacodynamic meta-analysis. PLoS Med 15(6): e1002579. https://doi.org/10.1371/journal.pmed.1002579

Author Affiliations:

WorldWide Antimalarial Resistance Network, Bangkok, Thailand
Centre for Tropical Medicine and Global Health, University of Oxford, Oxford, United Kingdom
Institute for Global Health, University College London, London, United Kingdom
WorldWide Antimalarial Resistance Network, Cape Town, South Africa
Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa
Kenya Medical Research Institute-Wellcome Trust Research Programme, Kilifi, Kenya
Institute for Tropical Medicine, Eberhard Karls University of Tübingen, Tübingen, Germany
Malaria Research and Training Center, Department of Epidemiology of Parasitic Diseases, Faculty of Pharmacy, University of Science, Techniques and Technologies of Bamako, Bamako, Mali
Novartis, Basel, Switzerland
Novartis Pharmaceuticals, East Hanover, New Jersey, United States of America
Institut Pasteur du Cambodge, Phnom Penh, Cambodia
Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden
Department of Infectious Diseases, Danderyds Hospital, Stockholm, Sweden
Bandim Health Project, Bissau, Guinea-Bissau
Department of Paediatrics, Kolding Hospital, Kolding, Denmark
Department of Women's and Children's Health, International Maternal and Child Health, Uppsala University, Uppsala, Sweden
Muhimbili University of Health and Allied Sciences, Dar es Salaam, Tanzania
Karolinska Institutet, Stockholm, Sweden
Department of Pharmacology, University of Gothenburg, Gothenburg, Sweden
Pharmetheus, Uppsala, Sweden
UCSF School of Pharmacy, San Francisco, California, United States of America
Yale School of Public Health, New Haven, Connecticut, United States of America
Institute for Tropical Medicine and Joanna Briggs Institute Affiliate Centre for Evidence Based Health Care Evidence Synthesis and Translation Unit, Afya Research Africa, Nairobi, Kenya
International Development Research Centre, Ottawa, Ontario, Canada
Medical School, Faculty of Health and Medical Sciences, The University of Western Australia, Perth, Western Australia, Australia
Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia
Epicentre, Paris, France
Department of Infectious Disease Epidemiology, London School of Hygiene & Tropical Medicine, London, United Kingdom
Faculty of Science, University of Portsmouth, Portsmouth, United Kingdom
Lao-Oxford-Mahosot Hospital-Wellcome Trust Research Unit, Vientiane, Laos
Faculty of Postgraduate Studies, University of Health Sciences, Vientiane, Laos
UMR216 Institut de Recherche pour le Développement, Faculté de Pharmacie, Université Paris Descartes, Paris, France
Centre Hospitalier Universitaire, UMR Inserm 1094 NET, Limoges, France
Shoklo Malaria Research Unit, Mae Sot, Thailand
Myanmar Oxford Clinical Research Unit, Yangon, Myanmar
Amsterdam Medical Centre, Amsterdam, The Netherlands
WorldWide Antimalarial Resistance Network, Darwin, Northern Territory, Australia
Global and Tropical Health Division, Menzies School of Health Research, Darwin, Northern Territory, Australia
Charles Darwin University, Darwin, Northern Territory, Australia
Institute of Tropical Medicine, Nagasaki University, Nagasaki, Japan
WorldWide Antimalarial Resistance Network, Oxford, United Kingdom
Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand

In your coverage please use this URL to provide access to the freely available paper: http://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1002579

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