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 presence of mefloquine is likely, as co-artemether may be used following failure of antimalarial prophylaxis or treatment with mefloquine.


OBJECTIVE
The effects on the QTc interval were compared among treatment with three doses of mefloquine (500, 250, 250 mg over 12 h) followed by six doses 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 design in 14 healthy male subjects per dose group.


METHODS
Electrocardiograms (ECGs) were recorded before dosing and repeatedly thereafter. The Bazett formula was used to calculate the QTc interval. The maximum and average QTc intervals for the first, third and sixth dosing intervals of co-artemether treatment were compared among treatments. Drug plasma concentrations were determined at identical times with the ECG recordings for exploratory pharmacokinetic/pharmacodynamic evaluation.


RESULTS
No clinically relevant differences in the QTc interval were observed after sequential administration of mefloquine and co-artemether relative to either treatment given alone, and there were no clinically relevant study drug-related effects on the QTc interval after either treatment. Plasma drug measurements revealed adequate systemic exposure to artemether, dihydroartemisinin, lumefantrine and mefloquine, well in line with the clinical setting. No correlation between the length of the QTc interval and plasma drug concentrations was found for any of the compounds.


CONCLUSIONS
Untoward effects on the QTc interval are unlikely to occur when co-artemether is administered following prophylaxis or treatment with mefloquine.
Bindschedler
M
M
Novartis Pharma Ltd, Research and Development Department, Basel, Switzerland. margaretha.bindschedler@pharma.novartis.com
Lefèvre
G
G
Ezzet
F
F
Schaeffer
N
N
Meyer
I
I
Thomsen
M S
MS
D000328:Adult; D000962:Antimalarials / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D000077549:Artemether; D000077611:Artemether, Lumefantrine Drug Combination; D037621:Artemisinins; D002851:Chromatography, High Pressure Liquid; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004338:Drug Combinations; D004347:Drug Interactions; D004562:Electrocardiography; D004983:Ethanolamines; D005449:Fluorenes / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects*; D006801:Humans; D008297:Male; D015767:Mefloquine / Q000493:pharmacokinetics / Q000494:pharmacology*; D008875:Middle Aged; D012717:Sesquiterpenes / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*
D000962:Antimalarials; D000077611:Artemether, Lumefantrine Drug Combination; D037621:Artemisinins; D004338:Drug Combinations; D004983:Ethanolamines; D005449:Fluorenes; D012717:Sesquiterpenes; D000077549:Artemether; D015767:Mefloquine