Disposition Kinetics of Intravenous Halofantrine-HCl in an Animal Model

Abstract

The disposition kinetics of intravenous halofantrine-HCl was studied in beagle dogs. In a dose-ranging study, three dose levels of halofantrine, 2.5 mg/kg, 5 mg/kg, and 10 mg/kg, were administered intravenously by infusion pump over 10 min or 2 h. the mode of intravenous administration of halofantrine was well tolerated by all animals. the 5 mg/kg dose infused over a period of 10 min produced adequate blood and plasma levels for pharmacokinetic analysis. therefore, this dose and infusion rate was employed in the definitive study.

The disposition of halofantrine followed a tri-exponential decline. the mean (± SD) elimination clearance is 15.7 ± 4.3 L/h for blood and 12.9 ± 2.6 L/h for plasma; while the steady-state volume of distribution for blood and plasma are 275.7 ± 165.9 L and 402.0 ± 205.6 L respectively. the terminal elimination half-lives in blood and plasma are 111.3 ± 72.1 h for blood and 192.8 ± 104.5 h for plasma.

Halofantrine was observed to be a low extraction drug with hepatic extraction ratio of approximately 0.25 and, is highly distributed in the peripheral compartments. It has a short mean residence time of about 0.3 h in the central compartment and there was evidence of preferential concentration of desbutyl-halofantrine in red blood cells. the implications of these in malaria therapy with halofantrine is unknown.