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AIM: To determine if reported lower plasma concentrations of artemisinin derivatives for malaria in pregnancy result from reduced oral bioavailability, expanded volume of distribution or increased clearance. METHODS: In a sequentially assigned crossover treatment study, pregnant women with uncomplicated falciparum malaria received i.v. artesunate (i.v. ARS) (4mgkg(-1) ) on the first day and oral ARS (4mgkg(-1) ) on the second, or, oral on the first and i.v. on the second, in both groups followed by oral ARS (4mgkg(-1) day(-1) ) for 5 days. Plasma concentrations of ARS and dihyroartemisinin (DHA) were measured by liquid chromatography-mass-spectrometry on days 0, 1, 2 and 6. Controls were the same women restudied when healthy (3 months post partum). RESULTS: I.v. ARS administration resulted in similar ARS and DHA pharmacokinetics in pregnant women with malaria (n= 20) and in controls (n= 14). Oral administration resulted in higher total drug exposure in pregnancy [AUC (95% CI) in (ngml(-1) h)/(mgkg(-1) )] of 55.1 (30.1, 100.0) vs. 26.5 (12.2, 54.3) for ARS, P= 0.002 and 673 (386, 1130) vs. 523 (351, 724) for DHA, P= 0.007. The corresponding median absolute oral bioavailability (F%) was 21.7 (12.6, 75.1) vs. 9.9 (6.0, 36.81) for ARS (P= 0.046) and 77.0 (42.2, 129) vs. 72.7 (42.0, 87.7) for DHA, P= 0.033. Total DHA exposure was lower at day 6 in pregnant women with malaria (P < 0.001) compared with day 0 or 1, but not in the controls (P= 0.084). CONCLUSIONS: This study demonstrates the effects of malaria on oral ARS drug disposition are greater than those of pregnancy. This probably results from a disease related reduction in first pass metabolism. The data are reassuring regarding current dosing recommendations.

Original publication

DOI

10.1111/j.1365-2125.2011.04103.x

Type

Journal article

Journal

Br J Clin Pharmacol

Publication Date

03/2012

Volume

73

Pages

467 - 477

Keywords

Adolescent, Adult, Antimalarials, Artemisinins, Artesunate, Biological Availability, Dose-Response Relationship, Drug, Female, Humans, Malaria, Falciparum, Metabolic Clearance Rate, Postpartum Period, Pregnancy, Pregnancy Complications, Parasitic, Severity of Illness Index, Young Adult