Artesunate/dihydroartemisinin pharmacokinetics in acute falciparum malaria in pregnancy: absorption, bioavailability, disposition and disease effects.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Lowered plasma concentrations of artesunate have been reported in uncomplicated malaria in pregnancy which could risk the life of the mother and fetus. • The reason for lowered plasma concentrations in pregnancy is unexplained. • Oral artesunate is hydrolyzed rapidly in the stomach to the biologically active metabolite dihyroartemisinin. WHAT THIS STUDY ADDS • Following i.v. artesunate administration for malaria in pregnancy the disposition of artesunate and dihydroartemisinin were similar to controls (the same women studied post partum without malaria). • Higher concentrations of artesunate and dihydroartemisinin were observed after oral administration i.e the disease reduced the pre-systemic metabolism of artesunate. • This study did not confirm previous reports and is reassuring regarding current dosing for artesunate in pregnancy. 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) (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). 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 (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). 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.