Stereoselective halofantrine disposition and effect:concentration‐related QTc prolongation

Abstract

Aims 1) To characterize the variability of multiple-dose halofantrine pharmacokinetics over time in healthy adults, 2) to correlate the pharmacodynamic measure electrocardiographic (ECG) QT interval with (+)-and (x)-halofantrine plasma concentration and 3) to evaluate the safety and tolerance of halofantrine hydrochloride given over time to healthy adults. Methods Twenty-one healthy subjects were enrolled and 13 completed the study (180 days). Subjects received either 500 mg of racemic halofantrine once daily in the fasted state for 42 days, or placebo, and then halofantrine washout was documented for the following 138 days. Pharmacokinetic and pharmacodynamic (ECG QTc) measurements were obtained. Results Mean accumulation half-times (days) for halofantrine were: 7.0t4. [(x)-halofantrine]. Peak plasma concentrations of both (+)-and (x)-halofantrine were attained at 6 h and maximal ECG QTc prolongation was at 4±8 h following drug administration. Fourteen of 16 subjects who received active drug had ECG QTc prolongation that was positively correlated with both (+)-and (x)-halofantrine concentration. The ®ve subjects who received placebo had no demonstrable change in ECG QTc throughout the study.Conclusions Halofantrine accumulates extensively and shows high intersubject pharmacokinetic variability, is associated with concentration-related ECG QTc prolongation in healthy subjects, and is clinically well tolerated in this subject group.

Does stereoselective lymphatic absorption contribute to the enantioselective pharmacokinetics of halofantrine In Vivo?

“…These findings likely reflect a gradual change to the proportion of the (+) enantiomer present in systemic blood. Previous data have shown that systemic levels of the (+)-Hf enantiomer in both human and rat are approximately 1.5 times higher than its antipode [1][2][3][4][5][6][7], and preliminary plasma assays performed in our laboratory have indicated that the same trend is followed in the dog (data not shown). At later time periods, when intestinal lymphatic transport has slowed, an increasing proportion of the Hf in thoracic lymph is present as a result of equilibration of Hf across lymphatic and blood capillaries.…”

“…relative enrichment of the (+)-enantiomer (data not shown) [1][2][3][4][5][6][7]. transport of the drug-lipoprotein complex via the intestinal lymphatic to the thoracic lymph.…”

Stereoselective halofantrine and desbutylhalofantrine disposition in the rat: cardiac and plasma concentrations and plasma protein binding

“…Thus, the pharmacokinetic results of DHF enantiomers after administration of parent drug in rat are paralleled by those in humans, in which plasma concentrations of (+)-DHF exceed those of antipode [5,15,16].…”

Effects of tetracycline on the pharmacokinetics of halofantrine in healthy volunteers

“…ECGs were recorded at 4,8,12, and 48 h following drug administration. Vital signs were measured throughout the study.…”

“…The declining sensitivity of P. falciparum to halofantrine may necessitate an increase in dosage, but the cardiotoxic effects of the drug are a major concern, especially as they are plasma concentration-dependent [4]. Therefore it is important that strategies are devised to prevent the further spread of halofantrine resistance and to delay its onset in areas where the drug is still effective.…”