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Stereoselective halofantrine disposition and effect: concentration-related QTc prolongation
D R Abernethy1, D L Wesche, J T Barbey
1Division of Clinical Pharmacology, Georgetown University School of Medicine, and the Walter Reed Army Institute for Research, Washington, DC., USA. abernethyd@grc.nia.nih.gov
British Journal of Clinical Pharmacology
|April 12, 2001
Summary
Halofantrine accumulates significantly in healthy adults, showing high variability and causing concentration-dependent ECG QTc prolongation. The drug was well-tolerated during this pharmacokinetic and pharmacodynamic study.
Area of Science:
- Pharmacology
- Clinical Pharmacology
- Drug Metabolism and Pharmacokinetics
Background:
- Halofantrine is an antimalarial drug with known pharmacokinetic variability.
- Understanding its accumulation and effects in healthy adults is crucial for safe dosing.
Purpose of the Study:
- To characterize halofantrine pharmacokinetics over time in healthy adults.
- To correlate electrocardiographic (ECG) QT interval changes with halofantrine plasma concentrations.
- To evaluate the safety and tolerance of multiple-dose halofantrine.
Main Methods:
- Twenty-one healthy subjects received daily halofantrine (500 mg) or placebo for 42 days.
- Pharmacokinetic and pharmacodynamic (ECG QTc) measurements were collected.
- Washout and tolerance were monitored for 138 days post-treatment.
Main Results:
- Halofantrine exhibited extensive accumulation with high intersubject pharmacokinetic variability.
- A positive correlation was observed between halofantrine concentration and ECG QTc prolongation.
- Fourteen of sixteen subjects on halofantrine showed QTc prolongation; placebo group showed no change.
Conclusions:
- Halofantrine demonstrates significant accumulation and high pharmacokinetic variability in healthy adults.
- The drug is associated with concentration-related ECG QTc prolongation.
- Halofantrine was clinically well-tolerated in this study population.