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Population Pharmacokinetics of Lumefantrine in Pregnant Women Treated with Artemether-Lumefantrine for Uncomplicated Plasmodium falciparum Malaria

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Tarning, Joel, McGready, Rose, Lindegardh, Niklas, Ashley, Elizabeth A., Pimanpanarak, Mupawjay, Kamanikom, Benjamas, Annerberg, Anna, Day, Nicholas P. J. +4 more·2009·Antimicrobial Agents and Chemotherapy
DOI 10.1128/aac.00195-09PMC PMC2737887
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Abstract

Artemether-lumefantrine has become one of the most widely used antimalarial drugs in the world. The objective of this study was to determine the population pharmacokinetic properties of lumefantrine in pregnant women with uncomplicated multidrug-resistant Plasmodium falciparum malaria on the northwestern border of Thailand. Burmese and Karen women (n= 103) with P. falciparum malaria and in the second and third trimesters of pregnancy were treated with artemether-lumefantrine (80/480 mg) twice daily for 3 days. All patients provided five capillary plasma samples for drug quantification, and the collection times were randomly distributed over 14 days. The concentration-time profiles of lumefantrine were assessed by nonlinear mixed-effects modeling. The treatment failure rate (PCR-confirmed recrudescent infections at delivery) was high; 16.5% (95% confidence interval, 9.9 to 25.1). The population pharmacokinetics of lumefantrine were described well by a two-compartment open model with first-order absorption and elimination. The final model included interindividual variability in all pharmacokinetic parameters and a linear covariate relationship between the estimated gestational age and the central volume of distribution. A high proportion of all women (40%, 41/103) had day 7 capillary plasma concentrations of <355 ng/ml (which corresponds to approximately <280 ng/ml in venous plasma), a threshold previously associated with an increased risk of therapeutic failure in nonpregnant patients in this area. Predictive modeling suggests that a twice-daily regimen given for 5 days would be preferable in later pregnancy. In conclusion, altered pharmacokinetic properties of lumefantrine contribute to the high rates of failure of artemether-lumefantrine treatment in later pregnancy. Dose optimization is urgently needed.

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  • Data available indicate that ACTs are relatively safe for the foetus when taken after the first trimester of pregnancy.

    “Data available indicate that ACTs are relatively safe for the foetus when taken after the first trimester of pregnancy.”

    From Malaria in pregnancy. (2013) · cites this paper as [129]

    The Abstract says that documented experience with more than 1,500 pregnant women supports using artemisinin derivatives in the second and third trimesters, and the Discussion calls ACTs the treatment of choice then. But the paper does not establish fetal safety specifically; it also says evaluation of newer fixed ACTs lags behind those recommendations. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • As for other antimalarial treatments, pharmacokinetics may be altered during pregnancy, with plasma concentrations lower than expected.

    “As for other antimalarial treatments, pharmacokinetics may be altered during pregnancy, with plasma concentrations lower than expected.129,139”

    From Malaria in pregnancy. (2013) · cites this paper as [129]

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Authors
Tarning, J., McGready, R., Lindegardh, N., Ashley, E. A., Pimanpanarak, M., Kamanikom, B., Annerberg, A., Day, N. P. J., Stepniewska, K., Singhasivanon, P., White, N. J., & Nosten, F.
Affiliations
  • Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
  • Mahidol University (TH)
  • Shoklo Malaria Research Unit (TH)
ORCID
Venue
Antimicrobial Agents and Chemotherapy
Publisher
American Society for Microbiology
Published
2009-09
Volume
53
Issue
9
Pages
3837-3846
ISSN
  • 0066-4804 (ISSN-L)
  • 1098-6596
DOI
10.1128/aac.00195-09
PMC
PMC2737887
OpenAlex
W2142803342
Cited by
99
References
3
Citations by year
2026: 3 · 2024: 2 · 2022: 3 · 2021: 4 · 2020: 4 · 2019: 5 · 2018: 7 · 2017: 3 · 2016: 7 · 2015: 8 · 2014: 11 · 2013: 8 · 2012: 13
FWCI
11.43
Type
journal article
Language
en
Open access
Licence
journals.asm.org/non-commercial-tdm-license (tdm)
Locations
  • Antimicrobial Agents and Chemotherapy (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Wellcome Trust
  • Mahidol University
Topics
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Malaria Research and Control
  • Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Pharmaceutical studies and practices
  • Health Sciences › Medicine › Pharmacology › Antibiotics Pharmacokinetics and Efficacy
Keywords
lumefantrine, artemether-lumefantrine, population pharmacokinetics, pregnancy, falciparum malaria, multidrug-resistant malaria, treatment failure, recrudescent malaria, gestational age, volume of distribution, dose optimization, northwestern Thailand
MeSH terms
Artemether, Lumefantrine, Adolescent, Adult, Animals, Antimalarials, Ethanolamines, Female, Fluorenes, Humans, Pregnancy, Logistic Models, Malaria, Falciparum, Artemisinins, Young Adult

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