Open Access Research

Population pharmacokinetics of artesunate and dihydroartemisinin in pregnant and non-pregnant women with malaria

Carrie A Morris1, Marie A Onyamboko2, Edmund Capparelli3, Matthew A Koch4, Joseph Atibu2, Vicky Lokomba2, Macaya Douoguih5, Jennifer Hemingway-Foday4, David Wesche6, Robert W Ryder3, Carl Bose7, Linda Wright8, Antoinette K Tshefu2, Steven Meshnick9 and Lawrence Fleckenstein1*

Author Affiliations

1 University of Iowa, College of Pharmacy, 115 South Grand Avenue, Iowa City, IA 52242, USA

2 Kinshasa School of Public Health, Kinshasa, The Democratic Republic of Congo

3 University of California, San Diego, CA, USA

4 RTI International, Research Triangle Park, NC, USA

5 Aeras Global TB Vaccine Foundation, Rockville, MD, USA

6 David Wesche Consulting LLC, Ann Arbor, MI, USA

7 University of North Carolina at Chapel Hill, NC, USA

8 National Institute of Child Health and Human Development, NIH, Rockville, MD, USA

9 UNC Gillings School of Global Public Health Department of Epidemiology, Chapel Hill NC, USA

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Malaria Journal 2011, 10:114  doi:10.1186/1475-2875-10-114

Published: 8 May 2011

Abstract

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.