Aims To investigate the pharmacokinetic and pharmacodynamic properties of artemether and benflumetol in a fixed combination tablet (CGP 56697) and to offer an explanation for the lower than expected cure rate in a Thai clinical trial. Methods Two hundred and sixty patients were enrolled into a randomized, doubleblind, parallel group, dose-finding trial. CGP 56697 was given orally, either as: A, 4×4 tablets over 48 h; B, 4×2 tablets over 48 h or C, 3×4 tablets over 24 h. Each tablet contained artemether 20 mg amd benflumetol 120 mg. The pharmacokinetics were determined using a population-based approach combining full profiles (42 patients) and sparse data (218 patients). Parasite clearance time and 28 day cure rate were correlated with the derived 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 (0.43) h. The variability in bioavailability of artemether and dihydroartemisinin was large both between doses and between patients, but was less pronounced for benflumetol. Compared with the first dose, benflumetol bioavailability was estimated to increase three-fold by the third and fourth doses. Higher artemether or dihydroartemisinin AUC 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 pharmacokinetic and pharmacodynamic properties of benflumetol and artemether differ markedly. Benflumetol AUC is associated with cure and the effect of benflumetol when coadministered with artemether is to prevent recrudescence. The mode of action of benflumetol is consistent with its longer elimination half-life. A short course of low-dose artemether, which is rapidly absorbed and has a short elimination half-life, produced effective parasite clearance. The complementary pharmacokinetic and pharmacodynamic properties of benflumetol and artemether was the main rationale for developing a fixed-dose combination. While the 4×4 dose regimen is very effective in most endemic areas, the poorer absorption (2.5 fold lower than in China) and the more resistant parasites in Thailand require higher doses of this drug.

Abstract. The efficacy-safety and pharmacokinetics of the six-dose regimen of artemether-lumefantrine (Coartem/ Riamet; Novartis Pharma AG, Basel, Switzerland) were assessed in a randomized trial in 219 patients (Ն 12 years old) with acute, uncomplicated Plasmodium falciparum malaria in Thailand. One hundred and sixty-four patients received artemether-lumefantrine and 55 received the standard treatment combination of mefloquine-artesunate. Both drugs induced rapid clearance of parasites and malaria symptoms. The 28-day cure rates were 95.5% (90% confidence interval [CI] ϭ 91.7, 97.9%) for artemether-lumefantrine and 100% (90% CI ϭ 94.5, 100%) for mefloquine-artesunate. This high-dose regimen of artemether-lumefantrine was very well tolerated, with very good compliance. The most frequent adverse events were headache, dizziness, nausea, abdominal pain, dyspepsia, vomiting, and skin rash. Overall, only 2% of patients in both groups showed QTc prolongations but without any cardiac complication, and no differences were seen between patients with and without measurable baseline plasma levels of quinine or mefloquine. Plasma levels of artemether, dihydroartemisinin, and lumefantrine were consistent with historical data for the same dose regimen, and were higher, particularly for lumefantrine, than those previously observed with the four-dose regimen, explaining the greater efficacy of the six-dose regimen in a drug-resistant setting. These results confirm the excellent safety and efficacy of the six-dose regimen of artemether-lumefantrine in the treatment of multidrug-resistant P. falciparum malaria.

The efficacy and safety of the 6-dose regimen of artemether-lumefantrine were assessed in an open randomized trial in children and adults presenting with acute, uncomplicated Plasmodium falciparum malaria in Thailand between November 1997 and March 1998. 200 patients were enrolled in 2 centres: 150 received artemether-lumefantrine (i.e., a median total dose of 9.6 mg/kg [interquartile range 8.7-10.7] and 57.9 mg/kg of lumefantrine [52.4-64.0]) and 50 the standard combination of artesunate (12 mg/kg over 3 d) and mefloquine (25 mg/kg). All patients had rapid initial clinical and parasitological responses. The 28 d cure rates were high: 97.7% (95% confidence interval [95% CI] 93.5-99.5%) for artemether-lumefantrine and 100% (95% CI 92.5-100%) for artesunate-mefloquine. The 6-dose regimen of artemether-lumefantrine was better tolerated than, and as effective as, artesunate-mefloquine, the current standard treatment in this area of multidrug-resistant P. falciparum malaria.

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SummaryA randomized, open trial involving 260 Tanzanian children, aged 1᎐5 years, with acute Plasmodium falciparum malaria was conducted to evaluate the efficacy of the combination antimalarial CGP 56697 (artemether and benflumetol), and to compare it with chloroquine, the standard drug used for malaria treatment in the Kilombero area. Children who had received rescue medication within the first 48 h or had a negative slide at the same time were excluded. Seven-day parasitological cure rates were 94% (95% CI 88᎐97.5) for CGP 56697 and 35.4% (95% CI 25.9᎐45.8) for chloroquine. Using the same definition, the 14-day parasitological cure rates were 86.4% (95% CI 78.5᎐92.2) for CGP 56697 and 10.3% (95% CI 5.1᎐18.1) for chloroquine. Gametocytes were more effectively suppressed by CGP 56697 than by chloroquine. There were no major adverse events with either drug. CGP 56697 is highly efficacious against P. falciparum in this area of Tanzania. The study contributes to the discussion on treatment strategies, particularly whether chloroquine may still fulfil its role as first-line drug in an area of high malaria transmission and very high levels of chloroquine resistance.