Evaluation of the impact of altered lipoprotein binding conditions on halofantrine induced QTc interval prolongation in an anaesthetized rabbit model

Abstract

Abstract Halofantrine has been observed to cause QT interval prolongation in susceptible patients and the effect has most commonly been observed after post-prandial administration. Halofantrine-induced QT prolongation occurs in conjunction with a significant increase in plasma halofantrine concentrations and an increase in halofantrine association with post-prandial plasma lipoproteins. The increased association of halofantrine with post-prandial lipoproteins is accompanied by a marked change in drug distribution between the different plasma lipoprotein fractions. This study was designed to evaluate the putative role of myocardium-based lipoprotein receptor-mediated uptake of lipoproteins as a possible contributing factor to the observed effect of halofantrine on QT intervals. The extent of QT interval prolongation following intravenous halofantrine administration (10 mg kg−1) to normolipidaemic (fasted) or hyperlipidaemic (induced with Intralipid infusion) anaesthetized New Zealand White rabbits (n = 6) was determined, as was the distribution of halofantrine between the plasma lipoprotein classes. The results, however, were in contrast to the suggested hypothesis since the QT interval was reduced (and not increased) after halofantrine administration to hyperlipidaemic rabbits relative to fasted rabbits. Therefore, it is unlikely that lipoprotein-based uptake of halofantrine into the myocardium is a major contributor to the previously observed increase in QT prolongation after post-prandial administration of halofantrine.