Pharmacokinetics of dihydroartemisinin following oral artesunate treatment of pregnant women with acute uncomplicated falciparum malaria

Objective: To determine the pharmacokinetic properties of dihydroartemisinin (DHA) following oral artesunate treatment in women with recrudescent multidrug resistant falciparum malaria, in the second and third trimesters of pregnancy. Methods: Serial plasma concentrations of artesunate and DHA were measured in 24 women after the final dose of a 3 day treatment with artesunate (4 mg kg(-1) day(-1)) and atovaquone (20 mg kg(-1) day(-1)) plus proguanil (8 mg kg(-1) day(-1)), daily. Conventional non-compartmental modelling and a population one-compartment pharmacokinetic model were applied to the data. Results: Artesunate was very rapidly eliminated. For DHA the median [90% range] estimate of oral clearance (CI/F) was 4.0 [0.8-20.7] 1 hour(-1) kg(-1), total apparent volume of distribution (Vd/f) was 3.4 [0.9-60.7] l/kg, and terminal elimination half-life was 1.0 [0.6-2.4] h. Conclusion: The kinetics of DHA are modified by pregnancy. The plasma levels of the active antimalarial metabolite DHA are lower than reported previously in non-pregnant adults. Dose-optimisation studies in pregnant women are needed.