Potentiation of halofantrine-induced QTc prolongation by mefloquine: correlation with blood concentrations of halofantrine.
1. The antimalarial drug halofantrine can prolong the QT interval and this may be enhanced by prior use of mefloquine. This possible interaction has been investigated by examining the effects of halofantrine and mefloquine alone and in combination. 2. In anaesthetized rabbits (n=6 per group), halofantrine given as bolus doses of 1, 3, 10, and 30 mg kg(-1) at 25 min intervals dose-dependently prolonged the rate-corrected QT (QTc) interval from 313+/-12 ms pre-drug to 410+/-18 ms after the highest dose. Similar doses of mefloquine did not alter QTc intervals significantly. The highest dose of mefloquine (30 mg kg(-1)) caused cardiac contractile failure. 3. Pretreatment with 3 mg kg(-1) mefloquine 25 min before the first dose of halofantrine potentiated the effects of all doses of halofantrine on QTc intervals. 4. The blood concentrations of halofantrine were two to six times higher in the group pretreated with mefloquine compared to the halofantrine alone group; e.g. 1.03+/-0.17 and 0.16+/-0.02 microM respectively after 1 mg kg(-1) halofantrine. There was a significant correlation between blood halofantrine concentrations and QTc intervals (r=0.673). Even after making allowance for overestimation of the potency of halofantrine that may result from the hypokalaemia that is prevalent in anaesthetized rabbits, these effects occurred with concentrations of halofantrine that are found in clinical use. 5. These data indicate clearly that while mefloquine does not alter QTc intervals itself, it does enhance the effects of halofantrine by increasing the circulating concentration of halofantrine.
Lightbown
I D
ID
Department of Pharmacology and Therapeutics, The University of Liverpool, Ashton Street, Liverpool L69 3GE.
Lambert
J P
JP
Edwards
G
G
Coker
S J
SJ
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000962:Antimalarials / Q000009:adverse effects*; D001784:Blood Gas Analysis; D004357:Drug Synergism; D004562:Electrocardiography; D005260:Female; D006439:Hemodynamics / Q000187:drug effects; D006863:Hydrogen-Ion Concentration; D008133:Long QT Syndrome / Q000139:chemically induced*; D015767:Mefloquine / Q000009:adverse effects* / Q000097:blood; D010616:Phenanthrenes / Q000009:adverse effects* / Q000097:blood; D011188:Potassium / Q000097:blood; D011817:Rabbits
D000962:Antimalarials; D010616:Phenanthrenes; C023768:halofantrine; D011188:Potassium; D015767:Mefloquine