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 m ay be enhanced by prior use of mefloquine. This possible interaction has be en investigated by examining the effects of halofantrine and mefloquine alo ne and in combination. 2 In anaesthetized rabbits (n = 6 per group), halofantrine given as bolus d oses of 1, 3, 10, and 30 mg kg(-1) at 25 min intervals dose-dependently pro longed 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 a lter 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 in tervals. 4 The blood concentrations of halofantrine were two to six times higher in the group pretreated with mefloquine compared to the halofantrine alone gro up; e.g. 1.03 +/- 0.17 and 0.16 +/- 0.02 muM respectively after 1 mg kg(-1) halofantrine. There was a significant correlation between blood halofantri ne concentrations and QTc intervals (r = 0.673). Even after making allowanc e for overestimation of the potency of halofantrine that may result from th e hypokalaemia that is prevalent in anaesthetized rabbits, these effects oc curred with concentrations of halofantrine that are found in clinical use. 5 These data indicate clearly that while mefloquine does not alter QTc inte rvals itself, it does enhance the effects of halofantrine by increasing the circulating concentration of halofantrine.