Pharmacokinetics of halofantrine in man: effects of food and dose size.

Abstract

1 Plasma concentrations of halofantrine (Hf) and its putative principal plasma metabolite desbutyl halofantrine (Hfm) have been measured in two separate studies after oral administration of the hydrochloride salt. 2 Six healthy male volunteers each received single oral doses of 250, 500 and 1000 mg administered after an overnight fast. A washout period of at least 6 weeks was allowed between each dose. A further 250 mg single oral dose was administered to the same six subjects in a fasting state and after a standardised fatty meal in a randomised study, again with a washout period of at least 6 weeks. 3 AUC and maximum plasma concentration (Cmax) for Hf increased in proportion to the dose from 250-500 mg. This increase was non-proportional when the dose was increased from 500 to 1000 mg. For Hfm, in the dose range 250-500 mg, AUC but not Cmax increased in proportion in the increase in dose size. The increase in these parameters was nonproportional when the dose was increased from 500 to 1000 mg. Time to reach peak concentrations for Hf and Hfm and the elimination half-life of Hf remained unchanged across the dosage range. 4 Following a fatty meal, Cmax for Hf was increased from 184 ± 115 ,ug 1-1 (fasting) to 1218 ± 464 ,ug 1-1 (fed). AUC for Hf was increased from 3.9 ± 2.6 mg l-1 h (fasting) to 11.3 ± 3.5 mg 1-1 h following a fatty meal. The AUC for Hfm was also increased from 8.8 ± 3.5 mg I-1 h (fasting) to 10.7 ± 3.2 mg 1-1 h (fed). 5 Hf was not detected in urine, and -0.01% of the dose was present as Hfm. 6 These data suggest that after oral administration of Hf hydrochloride, linear pharmacokinetics are observed in the single dose range of 250-500 mg. The apparent non-linearity above 500 mg may be a function of the poor solubility of Hf. 7 The relative systemic availability of Hf is increased significantly in the presence of food of high fat content. The mechanism responsible for this effect and its clinical consequences remain to be established.

Pharmacokinetics of halofantrine in Thai patients with acute uncomplicated falciparum malaria.

“…Previous pharmacokinetic studies of halofantrine in man have shown considerable inter and intra individual variability in healthy volunteers (Broom, 1989;Fleckenstein et al, 1983;Milton etal., 1989). Oral bioavailability appears to be increased by food (Milton et al, 1989) and early clinical evaluations of halofantrine suggested that therapeutic failure was a consequence of wide variation in drug absorption. The maximum concentration of halofantrine observed in the present study was lower than that reported previously in healthy subjects (Broom, 1989).…”

Halofantrine pharmacokinetics in Kenyan children with non‐severe and severe malaria.

“…The relative bioavailability of HF is a function of food intake and type; fatty food increases HF absorption [6]. Our results may also reflect the effect of clinical malaria on appetite.…”

“…Both chloroquine [4] and mefloquine [5] have been administered successfully by this route to patients with severe malaria. However, plasma concentrations of HF following oral dosage vary considerably in healthy Caucasian adults [6] and in adult Thai with malaria, which may contribute to drug failure [7]. HF produces a lengthening of the ECG QT-interval [8], which is apparently dose-related [9], and may predispose to ventricular arrhythmias.…”

Halofantrin zur Behandlung der importierten Malaria bei nicht-immunen Reisenden

“…Da sich ferner eine Entwicklung zur sogenannten Stand-by-Therapie andeutet (9,29) Bei der Pharmakokinetik von Halofantrin fällt auf, daß es schlecht wasserlöslich ist; das erklärt die erhebliche Schwankungsbreite der Bioverfügbarkeit (6). In pharmakokinetischen Untersuchungen lagen die Serumspiegel nach Nahrungsaufnahme höher als im Nüchternzustand (6,12 …”