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Cited by 43Malaria Research and ControlPharmaceutical studies and practicesAntibiotics Pharmacokinetics and Efficacy

Population pharmacokinetics of Artemether and dihydroartemisinin in pregnant women with uncomplicated Plasmodium falciparum malaria in Uganda

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Tarning, Joel, Kloprogge, Frank, Piola, Patrice, Dhorda, Mehul, Muwanga, Sulaiman, Turyakira, Eleanor, Nuengchamnong, Nitra, Nosten, François +4 more·2012·Malaria Journal
DOI 10.1186/1475-2875-11-293PMC PMC3502166
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Abstract

BACKGROUND: Malaria in pregnancy increases the risk of maternal anemia, abortion and low birth weight. Approximately 85.3 million pregnancies occur annually in areas with Plasmodium falciparum transmission. Pregnancy has been reported to alter the pharmacokinetic properties of many anti-malarial drugs. Reduced drug exposure increases the risk of treatment failure. The objective of this study was to evaluate the population pharmacokinetic properties of artemether and its active metabolite dihydroartemisinin in pregnant women with uncomplicated P. falciparum malaria in Uganda. METHODS: Twenty-one women with uncomplicated P. falciparum malaria in the second and third trimesters of pregnancy received the fixed oral combination of 80 mg artemether and 480 mg lumefantrine twice daily for three days. Artemether and dihydroartemisinin plasma concentrations after the last dose administration were quantified using liquid chromatography coupled to tandem mass-spectroscopy. A simultaneous drug-metabolite population pharmacokinetic model for artemether and dihydroartemisinin was developed taking into account different disposition, absorption, error and covariate models. A separate modeling approach and a non-compartmental analysis (NCA) were also performed to enable a comparison with literature values and different modeling strategies. RESULTS: The treatment was well tolerated and there were no cases of recurrent malaria. A flexible absorption model with sequential zero-order and transit-compartment absorption followed by a simultaneous one-compartment disposition model for both artemether and dihydroartemisinin provided the best fit to the data. Artemether and dihydroartemisinin exposure was lower than that reported in non-pregnant populations. An approximately four-fold higher apparent volume of distribution for dihydroartemisinin was obtained by non-compartmental analysis and separate modeling compared to that from simultaneous modeling of the drug and metabolite. This highlights a potential pitfall when analyzing drug/metabolite data with traditional approaches. CONCLUSION: The population pharmacokinetic properties of artemether and dihydroartemisinin, in pregnant women with uncomplicated P. falciparum malaria in Uganda, were described satisfactorily by a simultaneous drug-metabolite model without covariates. Concentrations of artemether and its metabolite dihydroartemisinin were relatively low in pregnancy compared to literature data. However, this should be interpreted with caution considered the limited literature available. Further studies in larger series are urgently needed for this vulnerable group.

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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 [128]

    The Results (Demographic information; page unavailable) say that treatment was well tolerated by 21 women in their second and third trimesters, but do not report fetal outcomes. Searches for fetal safety and birth outcomes found no passage assessing whether ACTs are safe for the foetus after the first trimester. (LLM, conf=0.73)

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Authors
Tarning, J., Kloprogge, F., Piola, P., Dhorda, M., Muwanga, S., Turyakira, E., Nuengchamnong, N., Nosten, F., Day, N. P., White, N. J., Guerin, P. J., & Lindegardh, N.
Affiliations
  • Mahidol University (TH)
  • Epicentre Uganda (UG)
  • University of Maryland, Baltimore (US)
  • Mbarara University of Science and Technology (UG)
  • University of Oxford (GB)
ORCID
Venue
Malaria Journal
Publisher
Springer Science and Business Media LLC
Published
2012-08-22
Volume
11
Issue
1
Pages
293-293
ISSN
1475-2875 (ISSN-L)
DOI
10.1186/1475-2875-11-293
PMC
PMC3502166
OpenAlex
W2163837666
Cited by
43
References
3
Citations by year
2022: 1 · 2020: 4 · 2019: 3 · 2018: 7 · 2017: 2 · 2016: 4 · 2015: 5 · 2014: 10 · 2013: 5 · 2012: 1
FWCI
6.49
Type
journal article
Language
en
Open access
Licence
Locations
  • Malaria Journal (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • UCL Discovery (University College London) (submittedVersion)
  • Greater South Information System
Funders
  • Bill and Melinda Gates Foundation
  • Wellcome Trust (089275, 093956, 093956/Z/10/Z)
  • European Commission
  • 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
artemether, dihydroartemisinin, population pharmacokinetics, malaria in pregnancy, Plasmodium falciparum, lumefantrine, drug exposure, volume of distribution, absorption model, Uganda, antimalarial drugs, treatment failure risk, maternal outcomes, low birth weight, anemia in pregnancy
MeSH terms
Artemether, Lumefantrine, Administration, Oral, Adolescent, Adult, Antimalarials, Chromatography, Drug Therapy, Combination, Ethanolamines, Female, Fluorenes, Humans, Plasma, Pregnancy, Pregnancy Complications, Infectious, Mass Spectrometry, Uganda, Models, Statistical, Malaria, Falciparum, Artemisinins, Young Adult

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