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

Abstract

BackgroundThe 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.MethodsData 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.ResultsA 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%).ConclusionsIn 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.

Population Pharmacokinetics, Tolerability, and Safety of Dihydroartemisinin-Piperaquine and Sulfadoxine-Pyrimethamine-Piperaquine in Pregnant and Nonpregnant Papua New Guinean Women

“…Previous studies have shown that the pharmacokinetic properties of DHA after oral administration of artesunate may include lower drug exposure during treatment for malaria in pregnancy (58,59), consistent with data from the Thai study involving DHA-PQ, which revealed a reduction of 37.5% in relative DHA bioavailability in pregnancy (14). In contrast, we did not find an effect of pregnancy on DHA pharmacokinetics in a sample of women with relatively few malaria cases.…”

Population Pharmacokinetic and Pharmacodynamic Modeling of Artemisinin Resistance in Southeast Asia

“…A simple one-compartment model was employed to describe the concentration-time profiles of ARS and DHA, which was in agreement with previous studies (38). However, in some reports, peripheral compartment structures have been proposed for DHA.…”

Know your enemy: understanding the role of PfCRT in drug resistance could lead to new antimalarial tactics

“…This problem is exacerbated by the mismatch in pharmacokinetics between the partner drugs. Artemisinin and its derivatives have short half-lives in the body of between 45 min and 20 h [137,140], while drugs such as LM and MQ have much longer half-lives of 3-4 [141] and 14-28 days [142], respectively. As a consequence, ACT treatment success rates are highly dependent on the susceptibility of the parasite to the partner drug, and failure rates between 10 and 30% have been reported for all combinations [143] (although in some cases, limitations in bioavailability may also be a factor).…”