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PLoS Med. 2018 Jun 12;15(6):e1002579. doi: 10.1371/journal.pmed.1002579. eCollection 2018 Jun.

Artemether-lumefantrine dosing for malaria treatment in young children and pregnant women: A pharmacokinetic-pharmacodynamic meta-analysis.

Author information

1
WorldWide Antimalarial Resistance Network, Bangkok, Thailand.
2
Centre for Tropical Medicine and Global Health, University of Oxford, Oxford, United Kingdom.
3
Institute for Global Health, University College London, London, United Kingdom.
4
WorldWide Antimalarial Resistance Network, Cape Town, South Africa.
5
Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa.
6
Kenya Medical Research Institute-Wellcome Trust Research Programme, Kilifi, Kenya.
7
Institute for Tropical Medicine, Eberhard Karls University of Tübingen, Tübingen, Germany.
8
Malaria Research and Training Center, Department of Epidemiology of Parasitic Diseases, Faculty of Pharmacy, University of Science, Techniques and Technologies of Bamako, Bamako, Mali.
9
Novartis, Basel, Switzerland.
10
Novartis Pharmaceuticals, East Hanover, New Jersey, United States of America.
11
Institut Pasteur du Cambodge, Phnom Penh, Cambodia.
12
Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
13
Department of Infectious Diseases, Danderyds Hospital, Stockholm, Sweden.
14
Bandim Health Project, Bissau, Guinea-Bissau.
15
Department of Paediatrics, Kolding Hospital, Kolding, Denmark.
16
Department of Women's and Children's Health, International Maternal and Child Health, Uppsala University, Uppsala, Sweden.
17
Muhimbili University of Health and Allied Sciences, Dar es Salaam, Tanzania.
18
Karolinska Institutet, Stockholm, Sweden.
19
Department of Pharmacology, University of Gothenburg, Gothenburg, Sweden.
20
Pharmetheus, Uppsala, Sweden.
21
UCSF School of Pharmacy, San Francisco, California, United States of America.
22
Yale School of Public Health, New Haven, Connecticut, United States of America.
23
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.
24
International Development Research Centre, Ottawa, Ontario, Canada.
25
Medical School, Faculty of Health and Medical Sciences, The University of Western Australia, Perth, Western Australia, Australia.
26
Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.
27
Epicentre, Paris, France.
28
Department of Infectious Disease Epidemiology, London School of Hygiene & Tropical Medicine, London, United Kingdom.
29
Faculty of Science, University of Portsmouth, Portsmouth, United Kingdom.
30
Lao-Oxford-Mahosot Hospital-Wellcome Trust Research Unit, Vientiane, Laos.
31
Faculty of Postgraduate Studies, University of Health Sciences, Vientiane, Laos.
32
UMR216 Institut de Recherche pour le Développement, Faculté de Pharmacie, Université Paris Descartes, Paris, France.
33
Centre Hospitalier Universitaire, UMR Inserm 1094 NET, Limoges, France.
34
Shoklo Malaria Research Unit, Mae Sot, Thailand.
35
Myanmar Oxford Clinical Research Unit, Yangon, Myanmar.
36
Amsterdam Medical Centre, Amsterdam, The Netherlands.
37
WorldWide Antimalarial Resistance Network, Darwin, Northern Territory, Australia.
38
Global and Tropical Health Division, Menzies School of Health Research, Darwin, Northern Territory, Australia.
39
Charles Darwin University, Darwin, Northern Territory, Australia.
40
Institute of Tropical Medicine, Nagasaki University, Nagasaki, Japan.
41
WorldWide Antimalarial Resistance Network, Oxford, United Kingdom.
42
Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.

Abstract

BACKGROUND:

The fixed dose combination of artemether-lumefantrine (AL) is the most widely used treatment for uncomplicated Plasmodium falciparum malaria. Relatively lower cure rates and lumefantrine levels have been reported in young children and in pregnant women during their second and third trimester. The aim of this study was to investigate the pharmacokinetic and pharmacodynamic properties of lumefantrine and the pharmacokinetic properties of its metabolite, desbutyl-lumefantrine, in order to inform optimal dosing regimens in all patient populations.

METHODS AND FINDINGS:

A search in PubMed, Embase, ClinicalTrials.gov, Google Scholar, conference proceedings, and the WorldWide Antimalarial Resistance Network (WWARN) pharmacology database identified 31 relevant clinical studies published between 1 January 1990 and 31 December 2012, with 4,546 patients in whom lumefantrine concentrations were measured. Under the auspices of WWARN, relevant individual concentration-time data, clinical covariates, and outcome data from 4,122 patients were made available and pooled for the meta-analysis. The developed lumefantrine population pharmacokinetic model was used for dose optimisation through in silico simulations. Venous plasma lumefantrine concentrations 7 days after starting standard AL treatment were 24.2% and 13.4% lower in children weighing <15 kg and 15-25 kg, respectively, and 20.2% lower in pregnant women compared with non-pregnant adults. Lumefantrine exposure decreased with increasing pre-treatment parasitaemia, and the dose limitation on absorption of lumefantrine was substantial. Simulations using the lumefantrine pharmacokinetic model suggest that, in young children and pregnant women beyond the first trimester, lengthening the dose regimen (twice daily for 5 days) and, to a lesser extent, intensifying the frequency of dosing (3 times daily for 3 days) would be more efficacious than using higher individual doses in the current standard treatment regimen (twice daily for 3 days). The model was developed using venous plasma data from patients receiving intact tablets with fat, and evaluations of alternative dosing regimens were consequently only representative for venous plasma after administration of intact tablets with fat. The absence of artemether-dihydroartemisinin data limited the prediction of parasite killing rates and recrudescent infections. Thus, the suggested optimised dosing schedule was based on the pharmacokinetic endpoint of lumefantrine plasma exposure at day 7.

CONCLUSIONS:

Our findings suggest that revised AL dosing regimens for young children and pregnant women would improve drug exposure but would require longer or more complex schedules. These dosing regimens should be evaluated in prospective clinical studies to determine whether they would improve cure rates, demonstrate adequate safety, and thereby prolong the useful therapeutic life of this valuable antimalarial treatment.

Conflict of interest statement

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, KH, FE and RB are employees of Novartis, the manufacturer of the drug that is the subject of this publication. EAA and NJW are members of the Editorial Board of PLOS Medicine. None of the authors declare any other conflict of interest.

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