Pharmacokinetics of benflumetol given as a fixed combination artemether-benflumetol (CGP 56697) in Thai patients with uncomplicated falciparum malaria

Abstract

The pharmacokinetics of benflumetol as a fixed combination, artemether-benflumetol (CGP 56697), following three regimens [regimen A: four tablets at 0, 8, 24 and 48 h (320 mg artemether, 1920 mg benflumetol); regimen B: two tablets at 0, 8, 24 and 48 h (160 mg artemether; 960 mg benflumetol); regimen C: four tablets at 0, 8 and 24 h (240 mg artemether; 1440 mg benflumetol)] were investigated in 39 patients with acute uncomplicated falciparum malaria. All patients showed a rapid initial response with a median parasite clearance time of 40, 41 and 39.5 h and a fever clearance time of 27.8, 32 and 24.5 h for regimens A, B and C, respectively. In nine patients (two, four and three patients in regimens A, B and C, respectively), however parasitemia reappeared in the peripheral blood smear between days 9 and 23. The pharmacokinetics of benflumetol were highly variable with coefficients of variation in pharmacokinetic parameters ranging from 14.9% to 144%. Absorption and elimination of benflumetol were relatively slow. Median C(max) per dose (first dose) was significantly higher in regimen B (6.29 ng/ml/mg dose) than in regimen A (2.6 ng/ml/mg dose) and regimen C (3.06 ng/ml/mg dose). Mean t(1/2z) in regimen C (2.65 h) was significantly shorter than in regimen A (4.5 h) and regimen B (3.89 h). In patients on regimens A and B who showed a sensitive response, plasma concentrations of benflumetol were significantly higher than in those with treatment failure.