Halofantrine clinical pharmacology

Halofantrine
HALFAN® FDA Package Insert
Description
Clinical Pharmacology
Microbiology
Indications and Usage
Contraindications
Warnings and Precautions
Adverse Reactions
Drug Interactions
Overdosage
Dosage and Administration
How Supplied

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Clinical Pharmacology

The interindividual variability in the pharmacokinetic parameters of halofantrine is very wide and has led to great difficulty in precisely determining the pharmacokinetic characteristics of this product.

Following administration of halofantrine hydrochloride tablets in single oral doses of 250 mg to 1000 mg to healthy volunteers, peak plasma levels were reached in 5 to 7 hours. High variability in the peak plasma levels was observed in all studies, suggesting erratic absorption from the gastrointestinal tract. An approximately seven-fold increase in peak plasma concentration and a three-fold increase in area under the curve (AUC) of halofantrine were obtained when a single 250 mg tablet was administered with high-fat food to healthy subjects.

Healthy volunteers who were given three oral doses of 500 mg of halofantrine hydrochloride (500 mg every 6 hours), when fed 2 hours before the second and third doses, had similar three- to five-fold increases in absorption. A mean Cmax of 3200 ng/mL (range 1555 to 4920 ng/mL) with a corresponding Tmax of 9 to 17 hours was attained following this multiple- dose regimen.

Halofantrine has a relatively long distribution phase with a half-life of 16 hours and a variable terminal elimination half-life of 6 to 10 days. The half-life of halofantrine varies considerably among individuals.

The primary metabolite of halofantrine is n-desbutyl halofantrine. Cmax values ranging from 310 to 410 ng/mL were observed to occur between 32 and 56 hours following oral administration of multiple doses of 500 mg halofantrine q6h for three doses. The apparent terminal elimination half-life of the metabolite is 3 to 4 days.

Based on animal studies, hepatobiliary clearance with fecal elimination of halofantrine parent compound and metabolite predominates. The extent to which halofantrine is bound to plasma proteins and the extent to which halofantrine is taken up into red blood cells are unknown. The pharmacokinetics of halofantrine in patients with compromised renal or hepatic function has not been investigated. The course of the anemia developed by a few malaria patients treated with halofantrine whose red blood cells were deficient in glucose-6-phosphate dehydrogenase (G6PD) was not different from that in malaria patients with normal G6PD values.

References

Adapted from the FDA Package Insert.