Malaria Journal | |
Population pharmacokinetics of artesunate and dihydroartemisinin in pregnant and non-pregnant women with malaria | |
Research | |
Macaya Douoguih1  David Wesche2  Marie A Onyamboko3  Joseph Atibu3  Antoinette K Tshefu3  Vicky Lokomba3  Linda Wright4  Jennifer Hemingway-Foday5  Matthew A Koch5  Steven Meshnick6  Edmund Capparelli7  Robert W Ryder7  Carrie A Morris8  Lawrence Fleckenstein8  Carl Bose9  | |
[1] Aeras Global TB Vaccine Foundation, Rockville, MD, USA;David Wesche Consulting LLC, Ann Arbor, MI, USA;Kinshasa School of Public Health, Kinshasa, The Democratic Republic of Congo;National Institute of Child Health and Human Development, NIH, Rockville, MD, USA;RTI International, Research Triangle Park, NC, USA;UNC Gillings School of Global Public Health Department of Epidemiology, Chapel Hill, NC, USA;University of California, San Diego, CA, USA;University of Iowa, College of Pharmacy, 115 South Grand Avenue, 52242, Iowa City, IA, USA;University of North Carolina at Chapel Hill, NC, USA; | |
关键词: Artesunate; Artemether; Artemisinin Derivative; Visual Predictive Check; Placental Malaria; | |
DOI : 10.1186/1475-2875-10-114 | |
received in 2010-11-24, accepted in 2011-05-08, 发布年份 2011 | |
来源: Springer | |
【 摘 要 】
BackgroundThe 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.MethodsData 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.ResultsA 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%).ConclusionsIn 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.
【 授权许可】
Unknown
© Morris et al; licensee BioMed Central Ltd. 2011. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
【 预 览 】
Files | Size | Format | View |
---|---|---|---|
RO202311109707573ZK.pdf | 3006KB | download |
【 参考文献 】
- [1]
- [2]
- [3]
- [4]
- [5]
- [6]
- [7]
- [8]
- [9]
- [10]
- [11]
- [12]
- [13]
- [14]
- [15]
- [16]
- [17]
- [18]
- [19]
- [20]
- [21]
- [22]
- [23]
- [24]
- [25]
- [26]
- [27]
- [28]
- [29]
- [30]
- [31]