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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
Population pharmacokinetics of artesunate and dihydroartemisinin in pregnant and non-pregnant women with malaria
Malaria Journal, Volume 10, Article 114, Year 2011
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Description
Background: The World Health Organization endorses the use of artemisinin-based combination therapy for treatment of acute uncomplicated falciparum malaria in the second and third trimesters of pregnancy. However, the effects of pregnancy on the pharmacokinetics of artemisinin derivatives, such as artesunate (AS), are poorly understood. In this analysis, the population pharmacokinetics of oral AS, and its active metabolite dihydroartemisinin (DHA), were studied in pregnant and non-pregnant women at the Kingasani Maternity Clinic in the DRC. Methods. Data were obtained from 26 pregnant women in the second (22 - 26 weeks) or the third (32 - 36 weeks) trimester of pregnancy and from 25 non-pregnant female controls. All subjects received 200 mg AS. Plasma AS and DHA were measured using a validated LC-MS method. Estimates for pharmacokinetic and variability parameters were obtained through nonlinear mixed effects modelling. Results: A simultaneous parent-metabolite model was developed consisting of mixed zero-order, lagged first-order absorption of AS, a one-compartment model for AS, and a one-compartment model for DHA. Complete conversion of AS to DHA was assumed. The model displayed satisfactory goodness-of-fit, stability, and predictive ability. Apparent clearance (CL/F) and volume of distribution (V/F) estimates, with 95% bootstrap confidence intervals, were as follows: 195 L (139-285 L) for AS V/F, 895 L/h (788-1045 L/h) for AS CL/F, 91.4 L (78.5-109 L) for DHA V/F, and 64.0 L/h (55.1-75.2 L/h) for DHA CL/F. The effect of pregnancy on DHA CL/F was determined to be significant, with a pregnancy-associated increase in DHA CL/F of 42.3% (19.7 - 72.3%). Conclusions: In this analysis, pharmacokinetic modelling suggests that pregnant women have accelerated DHA clearance compared to non-pregnant women receiving orally administered AS. These findings, in conjunction with a previous non-compartmental analysis of the modelled data, provide further evidence that higher AS doses would be required to maintain similar DHA levels in pregnant women as achieved in non-pregnant controls. © 2011 Morris et al; licensee BioMed Central Ltd.
Authors & Co-Authors
Morris, Carrie A.
United States, Iowa City
University of Iowa
Onyamboko, Marie A.
Congo, Kinshasa
Kinshasa School of Public Health
Capparelli, Edmund V.
United States, La Jolla
University of California, San Diego
Koch, Matthew A.
United States, Research Triangle Park
Rti International
Atibu, Joseph
Congo, Kinshasa
Kinshasa School of Public Health
Lokomba, Victor
Congo, Kinshasa
Kinshasa School of Public Health
Douoguih, MacAya
United States, Rockville
Aeras Global tb Vaccine Foundation
Hemingway-Foday, Jennifer J.
United States, Research Triangle Park
Rti International
Wesche, David L.
United States, Ann Arbor
David Wesche Consulting Llc
Ryder, Robert W.
United States, La Jolla
University of California, San Diego
Bose, Carl Lewis
United States, Chapel Hill
The University of North Carolina at Chapel Hill
Wright, Linda L.
United States, Bethesda
National Institute of Child Health and Human Development Nichd
Tshefu, Antoinette Kitoto
Congo, Kinshasa
Kinshasa School of Public Health
Meshnick, Steven Richard
United States, Chapel Hill
The University of North Carolina at Chapel Hill
Fleckenstein, Lawrence L.
United States, Iowa City
University of Iowa
Statistics
Citations: 48
Authors: 15
Affiliations: 8
Identifiers
Doi:
10.1186/1475-2875-10-114
e-ISSN:
14752875
Research Areas
Health System And Policy
Infectious Diseases
Maternal And Child Health
Sexual And Reproductive Health
Study Design
Cross Sectional Study
Participants Gender
Female