Stereoselective halofantrine disposition and effect: Concentration-related QTc prolongation

Darrell R. Abernethy, David L. Wesche, Jean T. Barbey, Colin Ohrt, Sarina Mohanty, John C. Pezzullo, Brian G. Schuster

Research output: Contribution to journalArticle

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 (-)-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: 7.0±4.8 [(+)-halofantrine] and 7.3±4.8 [(-)-halofantrine]. Mean steady-state concentrations were: 97.6±52.0 ng ml-1 [(+)-halofantrine] and 48.5±20.8 [(-)-halofantrine]. Steady-state oral clearance was: 139±73 l h-1 [(+)-halofantrine] and 265±135 l h-1 [(-)-halofantrine]. Peak plasma concentrations of both (+)- and (-)-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 (-)-halofantrine concentration. The five 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.

Original languageEnglish (US)
Pages (from-to)231-237
Number of pages7
JournalBritish Journal of Clinical Pharmacology
Volume51
Issue number3
DOIs
StatePublished - May 12 2001

Keywords

  • Halofantrine
  • QTc
  • Stereoselective clearance

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

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    Abernethy, D. R., Wesche, D. L., Barbey, J. T., Ohrt, C., Mohanty, S., Pezzullo, J. C., & Schuster, B. G. (2001). Stereoselective halofantrine disposition and effect: Concentration-related QTc prolongation. British Journal of Clinical Pharmacology, 51(3), 231-237. https://doi.org/10.1046/j.1365-2125.2001.00351.x