Cardiac effects of co-artemether (artemether/lumefantrine) and mefloquine given alone or in combination to healthy volunteers

Co-artemether is an oral tablet of artemether (20 mg) and lumefantrine (120 mg) for the treatment of falciparum malaria. Administration in the presenc e of mefloquine is likely, as co-artemether may be used following failure o f antimalarial prophylaxis or treatment with mefloquine. Objective: The effects on the QTc interval were compared among treatment wi th three doses of mefloquine (500, 250, 250 mg over 12 h) followed by six d oses of co-artemether (6 x 4 tablets over 60 h) and either treatment alone. The study was performed in a randomised, double-blind, parallel group desi gn in 14 healthy male subjects per dose group. Methods: Electrocardiograms (ECGs) were recorded before dosing and repeated ly thereafter. The Bazett formula was used to calculate the QTc interval. T he maximum and average QTc intervals for the first, third and sixth dosing intervals of co-artemether treatment were compared among treatments. Drug p lasma concentrations were determined at identical times with the ECG record ings for exploratory pharmacokinetic/ pharmacodynamic evaluation. Results: No clinically relevant differences in the QTc interval were observ ed after sequential administration of mefloquine and co-artemether relative to either treatment given alone, and there were no clinically relevant stu dy drug-related effects on the QTc interval after either treatment. Plasma drug measurements revealed adequate systemic exposure to artemether, dihydr oartemisinin, lumefantrine and mefloquine, well in line with the clinical s etting. No correlation between the length of the QTc interval and plasma dr ug concentrations was found for any of the compounds. Conclusions: Untoward effects on the QTc interval are unlikely to occur whe n co-artemether is administered following prophylaxis or treatment with mef loquine.