Population pharmacokinetics of lumefantrine in pregnant women treated with artemether-lumefantrine for uncomplicated Plasmodium falciparum malaria
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 northwe...
Saved in:
Main Authors: | , , , , , , , , , , , |
---|---|
Other Authors: | |
Format: | Article |
Published: |
2018
|
Subjects: | |
Online Access: | https://repository.li.mahidol.ac.th/handle/123456789/27928 |
Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
Institution: | Mahidol University |
id |
th-mahidol.27928 |
---|---|
record_format |
dspace |
spelling |
th-mahidol.279282018-09-13T14:11:48Z Population pharmacokinetics of lumefantrine in pregnant women treated with artemether-lumefantrine for uncomplicated Plasmodium falciparum malaria Joel Tarning Rose McGready Niklas Lindegardh Elizabeth A. Ashley Mupawjay Pimanpanarak Benjamas Kamanikom Anna Annerberg Nicholas P.J. Day Kasia Stepniewska Pratap Singhasivanon Nicholas J. White François Nosten Mahidol University Churchill Hospital Shoklo Malaria Research Unit Medicine Pharmacology, Toxicology and Pharmaceutics 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. Copyright © 2009, American Society for Microbiology. All Rights Reserved. 2018-09-13T06:54:24Z 2018-09-13T06:54:24Z 2009-09-21 Article Antimicrobial Agents and Chemotherapy. Vol.53, No.9 (2009), 3837-3846 10.1128/AAC.00195-09 10986596 00664804 2-s2.0-70349119891 https://repository.li.mahidol.ac.th/handle/123456789/27928 Mahidol University SCOPUS https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=70349119891&origin=inward |
institution |
Mahidol University |
building |
Mahidol University Library |
continent |
Asia |
country |
Thailand Thailand |
content_provider |
Mahidol University Library |
collection |
Mahidol University Institutional Repository |
topic |
Medicine Pharmacology, Toxicology and Pharmaceutics |
spellingShingle |
Medicine Pharmacology, Toxicology and Pharmaceutics Joel Tarning Rose McGready Niklas Lindegardh Elizabeth A. Ashley Mupawjay Pimanpanarak Benjamas Kamanikom Anna Annerberg Nicholas P.J. Day Kasia Stepniewska Pratap Singhasivanon Nicholas J. White François Nosten Population pharmacokinetics of lumefantrine in pregnant women treated with artemether-lumefantrine for uncomplicated Plasmodium falciparum malaria |
description |
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. Copyright © 2009, American Society for Microbiology. All Rights Reserved. |
author2 |
Mahidol University |
author_facet |
Mahidol University Joel Tarning Rose McGready Niklas Lindegardh Elizabeth A. Ashley Mupawjay Pimanpanarak Benjamas Kamanikom Anna Annerberg Nicholas P.J. Day Kasia Stepniewska Pratap Singhasivanon Nicholas J. White François Nosten |
format |
Article |
author |
Joel Tarning Rose McGready Niklas Lindegardh Elizabeth A. Ashley Mupawjay Pimanpanarak Benjamas Kamanikom Anna Annerberg Nicholas P.J. Day Kasia Stepniewska Pratap Singhasivanon Nicholas J. White François Nosten |
author_sort |
Joel Tarning |
title |
Population pharmacokinetics of lumefantrine in pregnant women treated with artemether-lumefantrine for uncomplicated Plasmodium falciparum malaria |
title_short |
Population pharmacokinetics of lumefantrine in pregnant women treated with artemether-lumefantrine for uncomplicated Plasmodium falciparum malaria |
title_full |
Population pharmacokinetics of lumefantrine in pregnant women treated with artemether-lumefantrine for uncomplicated Plasmodium falciparum malaria |
title_fullStr |
Population pharmacokinetics of lumefantrine in pregnant women treated with artemether-lumefantrine for uncomplicated Plasmodium falciparum malaria |
title_full_unstemmed |
Population pharmacokinetics of lumefantrine in pregnant women treated with artemether-lumefantrine for uncomplicated Plasmodium falciparum malaria |
title_sort |
population pharmacokinetics of lumefantrine in pregnant women treated with artemether-lumefantrine for uncomplicated plasmodium falciparum malaria |
publishDate |
2018 |
url |
https://repository.li.mahidol.ac.th/handle/123456789/27928 |
_version_ |
1763488572120236032 |