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

Abstract

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.

Population Pharmacokinetics of Dihydroartemisinin and Piperaquine in Pregnant and Nonpregnant Women with Uncomplicated Malaria

“…A similar observation has previously been reported for dihydroartemisinin, with a proportional 5-fold reduction in both mean oral clearance and apparent volume of distribution detected in malaria patients compared to healthy volunteers when evaluated with noncompartmental analysis (36,39,40). This might be a result of a disease-related decrease in first-pass metabolism possibly compounded by reduced hepatic blood flow, as suggested for artesunate in acute malaria patients (32).…”

Population Pharmacokinetic and Pharmacodynamic Modeling of Artemisinin Resistance in Southeast Asia

“…However, previous detailed PK studies of oral and parenteral administration of ARS have demonstrated a clear malaria effect on the relative bioavailability thought to result from reduced first pass metabolism (40,41). The decreased absorption rate with increasing parasite density was unexpected and opposite to previous observations (39,(42)(43)(44)(45)(46)(47)(48). The underlying mechanism of this effect cannot be elucidated from data collected in this study.…”

Pregnancy-Associated Changes in Pharmacokinetics: A Systematic Review

“…Three of these drugs are part of the antimalarial drug group (pyrimethamine [199,200], sulfadoxine [199,200], and DHA [192–194,197,198]), two are antithrombotic drugs (unfractionated heparin [113,114] and low-molecular-weight heparin [46,114–117]), one is an antibiotic (ampicillin [67,68]), and the last is an anticancer chemotherapeutic drug (doxorubicin [205,216]). The average quality score of the consistent antibiotic and antithrombotic studies tended to be higher than the quality score of the inconsistent studies from the same group (14.4 versus 11.5, p < 0.05, and 16.4 versus 15.5, p = 0.119, for the antibiotic and antithrombotic drugs, respectively).…”