The pharmacokinetics and pharmacodynamics of atovaquone and proguanil for the treatment of uncomplicated falciparum malaria in third-trimester pregnant women

Objective: To investigate the pharmacokinetics, safety and efficacy of the recommended 3-day treatment regimen of Malarone in third-trimester pregnant women with acute uncomplicated falciparum malaria. Methods: Twenty-six pregnant women in their third trimester (gestational age: 24-34 weeks) with acute uncomplicated Plasmodium falciparum malaria who fulfilled the enrollment criteria were recruited from the antenatal clinics of Mae Sot Hospital, Tak Province, Thailand, (n=8) and the Tropical Diseases Research Centre, Ndola, Zambia (n=18). Patients were treated with four Malarone tablets (GlaxoSmithKline: each tablet contains 250 mg atovaquone and 100 mg proguanil) once daily for 3 consecutive days. Blood samples were taken for pharmacokinetic investigations of atovaquone, proguanil, and cycloguanil up to 288 h (day 14) after the last dose. Urine samples were collected for the evaluation of proguanil and cycloguanil 0-8, 8-16, 16-24 and 24-48 h after the last dose. Efficacy assessments included the clinical and parasitological evaluation of mothers and newborns. Adverse events were evaluated at each visit to the antenatal clinics. Results: Malarone appeared to be effective and well tolerated when used for the treatment of falciparum malaria in pregnant women. All patients showed prompt clinical improvement and the disappearance of parasitaemia after treatment. There were no serious adverse effects or unexpected adverse effects and no stillbirths or spontaneous abortions. The plasma concentration-time profiles of atovaquone and proguanil in most cases were best characterised by the two-compartment open model with zero-order input with/without absorption lag time and first-order elimination. There were no significant differences in any of the pharmacokinetic parameters of atovaquone, proguanil or cycloguanil between patients from Thailand and Zambia. For atovaquone, a C-max of 1.33-8.33 mu g/ml was reached at 2.0-9.3 h after the last dose on day 2. V/F, CL/F and t(1/2 beta) were 6.9-39.5 l/kg, 83-384 ml/h/kg, and 57.8-130.8 h, respectively. The C-max and t(max) values for proguanil versus cycloguanil were 383-918 versus 0-129 ng/ml and 3.3-8.6 versus 3-12 h, respectively. V/F, CL/F, and t(1/2 beta) values for proguanil were 10.7-34.0 l/kg, 431-1,662 ml/h/kg and 11.2-30.3 h. The CLR-CG, t(1/2z), (CG), proguanil/cycloguanil metabolic ratios, AUC ratios for proguanil to cycloguanil (AUC(PG/CG)) were 107.2-1,001 ml/h/kg, 5-95 ml/h/kg, 7.8-20.7 h, 5-57, and 4.7-20.2, respectively. Conclusion: The pharmacokinetics of atovaquone and cycloguanil appeared to be influenced by the pregnancy status, resulting in an decrease in the C-max and AUC of approximately twofold.