Halofantrine

Abstract

Halofantrine is an orally administered blood schizontocide which is active against both chloro-quine-sensitive and chloroquine-resistant plasmodia. Dose-finding and noncomparative clinical trials have confirmed the efficacy of halofantrine in the treatment of falciparum malaria in areas of chloroquine- and sulfonamide/pyrimethamine-resistant malaria and vivax malaria. However, poor results obtained in patients who failed mefloquine prophylaxis suggest that the efficacy of halofantrine may not extend to mefloquine-resistant P. falciparum, although more studies are needed to confirm this. Data concerning halofantrine in the treatment of P. ovale and P. malariae infections are still limited. One comparative study indicates that halofantrine has an efficacy equivalent to that of mefloquine and may be better tolerated. Halofantrine is generally well tolerated in both adults and children, the most common drugassociated effects being abdominal pain, pruritus, vomiting, diarrhoea, headache and rash, although it is difficult to distinguish between disease- and treatment-related events. The development of parasite resistance to halofantrine, like other blood schizontocides, is inevitable. Poor absorption resulting in variable peak plasma halofantrine concentrations, and possible cross-resistance with mefloquine, may accelerate the emergence of resistance to halofantrine. Thus, it is of primary importance that halofantrine is used only in areas where chloroquine- and sulfonamide/pyrimethamine-resistance are established in order to preserve and sustain its efficacy. If used with care, halofantrine will provide an important treatment option for falciparum malaria, a widespread parasitic disease associated with considerable morbidity against which the number of effective drugs available is being increasingly compromised by the spread of resistance. In vitro, halofantrine has demonstrated activity against both chloroquine-sensitive (IC₅₀ 1.5 to 2.5 µg/L) and chloroquine-resistant (1.3 to 3.9 µg/L) strains of Plasmodium falciparum. These observations are supported by in vivo data from animal models of both P. berghei and P. falciparum infections. Halofantrine demonstrated activity about 3 times greater than that of chloroquine in mice infected with P. berghei. In humans, halofantrine 250mg administered every 6 hours for 3 days cleared parasitaemia in volunteers experimentally infected with P. vivax and multidrug-resistant and chloroquine-sensitive strains of P. falciparum. Recrudescence occurred after single-dose treatment. Halofantrine is a blood schizontocide and thus is active against the erythrocytic stages of Plasmodium spp. Data concerning the possible mechanism of action of halofantrine are contradictory although there is some support for the formation of a halofantrine-ferriprotoporphyrin IX complex, a mode of action similar to that proposed for other blood schizontocides. Inhibition of a proton pump at the host-parasite interface has also been hypothesised as an alternative mode of action. Most endemic malarious areas are now affected by chloroquine resistance. While the susceptibility of P. falciparum to halofantrine has been confirmed in a number of countries, in vitro cross-resistance with mefloquine has been documented although the full clinical relevance of this observation has yet to be clarified. Halofantrine is poorly and variably absorbed. The rate and extent of absorption is dramatically improved with food. In patients with falciparum malaria, peak plasma concentrations of 0.9 to 1.2 mg/L were achieved after about 16 hours following treatment with a 3-dose oral regimen of halofantrine (500mg 6-hourly). Elimination half-lives of halofantrine and its pharmacologically active metabolite, N-desbutylhalofantrine, ranged from 91 to 113 and 79 to 118 hours, respectively; the long half-life of the metabolite may encourage the selection of resistant strains. Plasma clearance was 0.58 L/h/kg. According to animal data, halofantrine is distributed widely in tissues and is excreted mainly in the faeces. Dose-finding and noncomparative studies have confirmed the efficacy of halofantrine in the treatment of falciparum malaria in areas of chloroquine and sulfonamide/pyrimethamine resistance. Cure rates of 83 to 100% have been reported in noncomparative trials in adults and children after treatment with the recommended 3-dose regimen of halofantrine (500mg 6-hourly). Treatment is accompanied by clearance of parasitaemia within 34 to 78 hours and fever within 18 to 101 hours. Other symptoms of malaria also show evidence of improvement, usually on the first day of treatment. Splenomegaly and hepatomegaly cleared in around three-quarters of affected patients in the follow-up period after treatment. In an overview of 1474 patients with malaria, parasitaemia was not cleared in 0.5% of patients and the recrudescence rate was 5.8%. The majority of treatment failures observed with halofantrine have been attributed to incomplete drug absorption, although frequently there have been insufficient data to eliminate the possibility of decreased parasite susceptibility or resistance. In some studies, patients remained in endemic areas and recrudescence may have been attributable to reinfection. The efficacy of halofantrine in the treatment of P. vivax infections has also been established, but experience in the treatment of P. ovale and P. malariae infections is very limited. Halofantrine appears to be as effective as single-dose mefloquine in falciparum malaria according to one large comparative trial conducted in Thailand. However, the results of a more recent comparative trial were suggestive of parasite resistance to halofantrine in eastern Thailand. A failure rate of 30% with halofantrine in patients who failed mefloquine prophylaxis provides some support for in vitro data indicating that there is cross-resistance between halofantrine and mefloquine. Although further studies are needed to support these findings, these observations suggest that the activity of halofantrine may not be optimal against mefloquine-resistant P. falciparum. The incidence of treatment-related adverse events in almost 2000 patients treated with halofantrine was estimated to be 0.81/100 patients. The most commonly reported drug-related effects were abdominal pain, pruritus, vomiting, diarrhoea, headache and rash. However, the relationship between halofantrine treatment and adverse effects is difficult to determine in patients with malaria because many such symptoms are also disease-related. Pruritus associated with halofantrine treatment has been found to be milder, of shorter duration and to occur less frequently than that associated with chloroquine. This observation may be important for African patients, about 8 to 20% of whom are unable to tolerate chloroquine because of treatment-related pruritus. In animal studies, there has been no evidence of genotoxicity, teratogenicity or any effects on male fertility; however, embryotoxicity has been reported. The recommended dosage regimen of halofantrine is 500mg in adults or 8 mg/kg in children, administered orally for 3 doses at 6-hourly intervals. A second course of treatment given after 7 days is advised for nonimmune patients and young children. Halofantrine is contraindicated in pregnant and lactating women and is not recommended for use in causal or suppressive prophylactic regimens.