Artesunate/Dihydroartemisinin Pharmacokinetics in Acute Falciparum Malaria in Pregnancy: Absorption, Bioavailability, Disposition and Disease Effects

AIMTo 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.METHODSIn a sequentially assigned crossover treatment study, pregnant women with uncomplicated falciparum malaria received i. v. artesunate (i. v. ARS) (4 mg kg-1) on the first day and oral ARS (4 mg kg-1) on the second, or, oral on the first and i. v. on the second, in both groups followed by oral ARS (4 mg kg-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).RESULTSI. 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 (ng ml-1 h)/(mg kg-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).CONCLUSIONSThis 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.