Population pharmacokinetics and therapeutic response of CGP56697 (artemether plus benflumetol) in malaria patients

Aims To investigate the pharmacokinetic and pharmacodynamic properties of a rtemether and benflumetol in a fixed combination tablet (CGP 56697) and to offer an explanation for the lower than expected cure rate in a Thai clinic al trial. Methods Two hundred and sixty patients were enrolled into a randomized, dou ble-blind, parallel group, dose-finding trial. CGP 56697 was given orally, either as: A, 4 x 4 tablets over 48 h; B, 4 x 2 tablets over 48 h or C, 3 x 4 tablets over 24 h. Each tablet contained artemether 20 mg amd benflumeto l 120 mg. The pharmacokinetics were determined using a population-based app roach combining full profiles (42 patients) and sparse data (218 patients). Parasite clearance time and 28 day cure rate were correlated with the deri ved pharmacokinetic parameters. Results The median absorption half-life of benflumetol was 5.3 h, with a t( max) of 10 h and terminal elimination half-life of 4.5 days. For artemether (and its metabolite, dihydroartemisinin), the corresponding values were 1. 9 (1.9) h, 1.8 (1.2) h, and 0.84 (0.33) h. The variability in bioavailabili ty of artemether and dihydroartemisinin was large both between doses and be tween patients, but was less pronounced for benflumetol. Compared with the first dose, benflumetol bioavailability was estimated to increase three-fol d by the third and fourth doses. Higher artemether or dihydroartemisinin AU C was found to decrease parasite clearance time. Higher benflumetol AUC was found to significantly increase the chance of cure. Conclusions Using a population-based approach it was confirmed that the pha rmacokinetic and pharmacodynamic properties of benflumetol and artemether d iffer markedly. Benflumetol AUC is associated with cure and the effect of b enflumetol when coadministered with artemether is to prevent recrudescence. The mode of action of benflumetol is consistent with its longer eliminatio n half-life. A short course of low-dose artemether, which is rapidly absorb ed and has a short elimination half-life, produced effective parasite clear ance. The complementary pharmacokinetic and pharmacodynamic properties of b enflumetol and artemether was the main rationale for developing a fixed-dos e combination. While the 4 x 4 dose regimen is very effective in most endem ic areas, the poorer absorption (2.5 fold lower than in China) and the more resistant parasites in Thailand require higher doses of this drug.