Stereoselective halofantrine disposition and effect:concentration‐related QTc prolongation

• Published in: British journal of clinical pharmacology Vol. 51; no. 3; pp. 231 - 237
• Main Authors: Abernethy, Darrell R., Wesche, David L., Barbey, Jean T., Ohrt, Colin, Mohanty, Sarina, Pezzullo, John C., Schuster, Brian G.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Science Ltd 01.03.2001; Blackwell Science; Blackwell Science Inc
• Subjects: Adult; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antimalarials - blood; Antimalarials - chemistry; Antimalarials - pharmacokinetics; Antiparasitic agents; Biological and medical sciences; Dose-Response Relationship, Drug; Electrocardiography - drug effects; Female; halofantrine; Humans; Long QT Syndrome - metabolism; Male; Medical sciences; Metabolic Clearance Rate; Molecular Conformation; Pharmacokinetics/Pharmacodynamics; Pharmacology. Drug treatments; Phenanthrenes - blood; Phenanthrenes - chemistry; Phenanthrenes - pharmacokinetics; QTc; stereoselective clearance; Human; Antimalarial; QT interval; Healthy subject; Oral administration; Halofantrine; Multiple dose; Stereoselectivity; Activity concentration relation; Enantiomer; Parasiticid; Electrocardiography; Pharmacokinetics
• ISSN: 0306-5251; 1365-2125
• DOI: 10.1046/j.1365-2125.2001.00351.x

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.