The pharmacokinetics of atovaquone and proguanil in pregnant women with acute falciparum malaria

Abstract

Objective: To determine the pharmacokinetic properties of atovaquone, proguanil, and the triazine metabolite cycloguanil in women with recrudescent multi-drug resistant falciparum malaria during the second and third trimesters of pregnancy treated by artesunate-atovaquone-proguanil. Methods: Serial plasma concentrations of atovaquone, proguanil and cycloguanil were measured in 24 women at baseline and after the final dose of the 3-day treatment with atovaquone (20 mg/kg/day) plus proguanil (8 mg/ kg/day) plus artesunate (4 mg/kg/day) daily. Results: The triple combination was well tolerated and highly effective. The outcomes of pregnancy were all normal. Population mean (± SEM) oral clearance (Cl/F) estimates were 313 ± 33 ml/h/kg and 1109 ± 43 ml/h/kg, total apparent volume of distribution (Vd/F) 13.0 ± 1.3 l/kg and 22.9 ± 1.4 l/kg, and terminal elimination half-life; 29.1 h and 14.3 h, for atovaquone and proguanil, respectively. Using conventional and population pharmacokinetic analyses, Cl/F and Vd/F estimates for both drugs were approximately twice, and plasma concentrations less than half those reported previously in healthy subjects and patients with acute malaria. Conclusion: Artesunate-atovaquone-proguanil is a promising treatment for multi-drug resistant falciparum malaria during pregnancy, but the dose of atovaquone-proguanil may need to be increased.