A physicochemical Basis for the Effect of Food on the Absolute Oral Bioavailability of Halofantrine

Abstract

Halofantrine hydrochloride (Hf.HCl) is a highly lipophilic phenanthrenemethanol antimalarial. The poor and erratic absorption of Hf after oral administration has been implicated in some treatment failures. Food increases the oral bioavailability of Hf in humans approximately 3-5-fold, although neither the absolute bioavailability nor the basis for the food effect has been fully defined. In this study, the mean (+/-SD, n = 3) absolute oral bioavailability of 250 mg Hf.HCl tablets in beagles was 8.6 +/- 5.3% in the fasted state, which increased approximately 12-fold when administered postprandially. These data indicate that Hf.HCl is efficiently absorbed from the postprandial intestinal environment. The solubility and intrinsic dissolution rate of Hf.HCl were investigated as a function of bile salt concentration (sodium taurocholate, NaTC, 0-30 mM) and micellar composition (4:1 NaTC:lecithin). At premicellar (fasted) concentrations of NaTC (< 5 mM), the solubility and intrinsic dissolution rate were very low (< 15 micrograms/mL; < 0.01 microgram s-1 cm-2). At NaTC concentrations typical of the postprandial state, the solubility and dissolution rate improved dramatically. For example, solubility in 30 mM NaTC increased approximately 1000-fold relative to buffer control, with even greater enhancement (3000-fold) associated with mixed micellar systems. These data suggest that the improved absorption of Hf.HCl in the fed state is most likely due to the increased solubilization and dissolution of the drug in the presence of bile salt mixed micelles.