Potentiation of halofantrine-induced QTc prolongation by mefloquine: correlation with blood concentrations of halofantrine

Abstract

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.

Figure 1

Heart rate (a) and mean arterial blood pressure (b) measured at various time points in the four groups of anaesthetized rabbits receiving vehicle (Control), mefloquine (MQ), halofantrine (HF) or halofantrine after 3 mg kg⁻¹ mefloquine (HF+MQ). The arrows indicate the times at which bolus i.v. injections of 3 mg kg⁻¹ mefloquine (M), or 1, 3, 10, and 30 mg kg⁻¹ of mefloquine or halofantrine were given. Values are means with vertical bars indicating s.e.mean, n=6 per group.

Figure 2

QTc intervals measured at various time points in the four groups of anaesthetized rabbits receiving vehicle (Control), mefloquine (MQ), halofantrine (HF) or halofantrine after 3 mg kg⁻¹ mefloquine (HF+MQ). The arrows indicate the times at which bolus i.v. injections of 3 mg kg⁻¹ mefloquine (M), or 1, 3, 10, and 30 mg kg⁻¹ of mefloquine or halofantrine were given. Values are means with vertical bars indicating s.e.mean, n=6 per group. ^*P<0.05 compared with control group, ^#P<0.05 compared with halofantrine group at that time point, Kruskal-Wallis test.

Figure 3

Lead II ECG, arterial blood pressure (BP) and epicardial monophasic action potential (EpiMAP) measured (a) before drug administration, (b) 19 min after administration of 10 mg kg⁻¹ halofantrine and (c) 5 min after 30 mg kg⁻¹ halofantrine in one rabbit from the group pretreated with 3 mg kg⁻¹ mefloquine before receiving increasing doses of halofantrine. In (a) there is normal sinus rhythm but the P waves of each ECG complex are merged with the T wave of the preceding complex. In (b) there is 2 : 1 second degree atrio-ventricular (AV) block. Alternate P waves appear in the rising phase of the T wave of the preceding complex and the subsequent QRS complex is missing. (c) Illustrates second degree Mobitz type 1 (Wenkebach) AV block which is characterized by progressive lengthening of the PR interval until there is a missed QRS complex. The solid bars under the ECG complexes indicate the PR intervals. (b) and (c) also reveal halofantrine-induced increases in T wave amplitude and delays in repolarization during phase 3 of the epicardial monophasic action potentials.

Figure 4

The concentrations of halofantrine measured by high performance liquid chromatography in blood samples taken 20 min after administration of each dose of halofantrine from animals receiving halofantrine alone (HF) or halofantrine after 3 mg kg⁻¹ mefloquine (HF+MQ). Values are means with vertical bars indicating s.e.mean, n=6 per group. ^*P<0.05 compared halofantrine group, Kruskal – Wallis test.

Figure 5

Correlation between the individual values for QTc intervals measured 20 min after administration of each dose of halofantrine and the blood concentrations of halofantrine in samples obtained at those time points from animals receiving halofantrine alone (HF) or halofantrine after 3 mg kg⁻¹ mefloquine (HF+MQ).