ABSTRACT
OBJECTIVE: To determine the pharmacokinetic properties of dihydroartemisinin (DHA) following oral artesunate treatment in women with recrudescent multi-drug 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] l 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.
Subject(s)
Antimalarials/pharmacokinetics , Artemisinins/pharmacokinetics , Malaria, Falciparum/drug therapy , Pregnancy Complications, Parasitic/drug therapy , Sesquiterpenes/pharmacokinetics , Acute Disease , Adolescent , Adult , Analysis of Variance , Antimalarials/administration & dosage , Antimalarials/therapeutic use , Artemisinins/administration & dosage , Artemisinins/therapeutic use , Artesunate , Atovaquone/administration & dosage , Atovaquone/pharmacokinetics , Atovaquone/therapeutic use , Drug Combinations , Drug Resistance, Multiple , Drug Therapy, Combination , Female , Half-Life , Humans , Malaria, Falciparum/blood , Malaria, Falciparum/metabolism , Pregnancy , Pregnancy Complications, Parasitic/blood , Pregnancy Complications, Parasitic/metabolism , Pregnancy Outcome , Pregnancy Trimester, Second , Pregnancy Trimester, Third , Proguanil/administration & dosage , Proguanil/pharmacokinetics , Proguanil/therapeutic use , Sesquiterpenes/administration & dosage , Sesquiterpenes/therapeutic use , ThailandABSTRACT
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.
