Effect of a single oral dose of Fansidar on the pharmacokinetics of halofantrine in healthy volunteers: a preliminary report.

Abstract

In many countries multidrug resistant Plasmodium falciparum malaria is an increasing problem [1]. Halofantrine is a recent addition to the therapeutic arsenal [2] and it has already earned an important place in the treatment of uncomplicated, multidrug resistant disease [3]. However, in some countries there are reports of resistance to halofantrine [4, 5]. To prevent its further spread and to delay the onset of resistance to this new drug in areas not experiencing resistance, it would seem appropriate to recommend that halofantrine be used in combination with other antimalarial drugs. Halofantrine and sulphadoxine-pyrimethamine (Fansidar™) is one option. If so, assessing the clinical and pharmacokinetic profiles of this combination becomes mandatory for rational utilization of the drugs. This study examined the effect of Fansidar™ on single-dose halofantrine pharmacokinetics in healthy Papua New Guinean volunteers. Seven healthy male subjects (18–40 years; 45–70 kg), none of whom was on regular medication, volunteered to take part in the study. Each volunteer gave informed consent to participate in the study that was approved by the Ethics and Medical Research Committee of the Faculty of Medicine, University of Papua New Guinea. One day before drug administration, each subject had a physical examination, routine laboratory (haematologic and biochemical) investigations, excepting ECG tracings. The subjects were randomized to receive either halofantrine alone or halofantrine and Fansidar™ (sulphadoxine-500 mg, pyrimethamine 25 mg) in a simple crossover, two phased study design with an interval of not less than 4 weeks between treatments. On the first occasion, after an overnight fast, the subjects were randomized to receive halofantrine or coadministration of halofantrine and Fansidar. Fansidar™; (2 tablets) was given orally 15 min prior to a single dose of halofantrine (250 mg tablet × 2). Excepting for fluids, solids were not permitted until 2 h postdosing, and all drugs were coadministered with water (∼100 ml). Whole blood samples (5 ml) were collected into heparinized tubes at 0, 0.25, 0.5, 1, 2, 3, 4, 6, 8,12, and 24 h and on days 2, 3, 4, 5, 7, 14 and 28. Any adverse events were recorded especially gastrointestinal, central nervous system, cardiovascular, and dermatological and any other complaints possibly attributable to halofantrine. Plasma was separated and stored at −80° C until analysis within 6 months. Plasma concentrations of halofantrine and N-desbutylhalofantrine were determined by reverse-phase automated high performance liquid chromatography with Photodiode Array detection after direct liquid- phase extraction as described previously [6]. An on-line computer software program (Millennium, Waters™) was used to generate standard curves for halofantrine and desbutylhalofantrine from which, respective drug concentrations were calculated and read automatically. The internal standard was 2,4-dichloro-6-trifluoro-9-(2-dibutylamino) ethyl. Smith Kline-Beecham laboratories provided halofantrine, N-desbutylhalofantrine, and internal standard. Accuracy of the assay was calculated as the percentage difference between the known concentration in spiked samples and concentration measured in the assay. The intra-and interassay (between days) precision of the method ( 0.05). However, absorption half-life (t½,abs), terminal half-life (t½,z), total AUC(0,∞), and tmax values were similar on both occasions. Thus the data suggest that Fansidar™ increased the extent but not the rate of oral halofantrine absorption. Table 1 Pharmacokinetic parameters (arithmetic mean, 95% confidence interval) of halofantrine and desbutylhalofantrine in the presence or absence of Fansidar™; in seven healthy volunteers after a single oral dose administration of halofantrine HCl. These observations might indicate increases in peak plasma concentrations during multiple dose administration. Obviously, this would lead to relatively greater plasma concentration of halofantrine; a factor that might contribute to cardiotoxicity should halofantrine be used in combination with Fansidar™ for malaria treatment. Although electrocardiograms (ECG) were not done, minimal ECG changes with lengthening of QT interval without clinical symptoms are frequent and these changes, at least in ECG terms, are dose/concentration-dependent [8]. Therefore, it is one of the manufacturers recommendations that halofantrine should not be used in combination with drugs that prolong QT interval or in clinical situations likely to do so. The increases in the halofantrine Cmax and AUC(0,6h) values, obtained in the presence of a single dose of Fansidar™ appear not to cause any obvious clinical toxicity. The mechanism underlying such increases is unclear, but a possibility of enhanced halofantrine absorption following prior oral intake of Fansidar™ cannot be excluded and needs further investigation.