Halofantrine dosing

Khoo SM, Shackleford DM, Porter CJ, Edwards GA and Charman WN (2003) Intestinal Lymphatic Transport of Halofantrine Occurs After Oral Administration of a Unit-Dose Lipid-Based Formulation to Fasted Dogs. Pharm Res 20 pp 1460-1465. 

Halofantrine is usually well tolerated. Gastrointestinal complaints as well as pruritus and skin rashes may occur. It can prolong the QTc interval which can result in ventricular dysrythmias. Lume-fantrine has many similarities to halofantrine but seems not to prolong QTc. It is thus far only used in a fixed dose combination with artemether (see Section VI.a.2.5). 

Halofantrine hydrochloride, a phenanthrene-methanol, is effective against erythrocytic (but not other) stages of all four human malaria species. Oral absorption is variable and is enhanced with food. Because of toxicity concerns, it should not be taken with meals. Plasma levels peak 16 hours after dosing, and the half-life is about 4 days. Excretion is mainly in the feces. The mechanism of action of halofantrine is unknown. The drug is not available in the USA (although it has been approved by the FDA), but it is widely available in malaria-endemic countries. 

Halofantrine (three 500-mg doses at 6-hour intervals, repeated in 1 week for nonimmune individuals) is rapidly effective against... 

With exceptions, including halofantrine, DDT, and the lipophilic vitamins, the extent of lymphatic transport (as a proportion of the dose) is generally low. However, the compounds described in Table 5 are hydrophobic (as evidenced by the high log Ps), and their bioavailability is often low. Therefore, although the absolute extent of lymphatic transport may be low, the lymphatic contribution to the small fraction that is absorbed may be high, and alterations in the extent of lymphatic transport may have a significant effect on the extent of oral bioavailability. 

Halofantrine 8.5 >50 mg/mL (peanut oil) 50 xL peanut oil 16.7% 12 h Conscious rat/Mesen-teric lymph duct/ Oral dosing 102... 

The loading dose shovild not be given if the patient has received quinine, quinidine or mefloquine in the previous 24 h see also warnings about halofantrine (below). 

The effects on the QTc interval of single oral doses of halofantrine 500 mg and artemether 80 mg + lumefantrine 480 mg have been studied in 13 healthy men in a double-blind, randomized, crossover study (25). The length of the QT interval correlated positively with halofantrine exposure but was unchanged by co-artemether. 

Halofantrine is a phenanthrene-methanol derivative of an aminoalcohol, active against multidrug-resistant Plasmodium falciparum malaria. Halofantrine was known during World War II but was little used at that time. It is slowly and incompletely absorbed with peak concentrations 3.5-6 hours after dosing. Its absorption in its original formulation was unpredictable (SEDA-13, 820). 

Dose-finding studies with halofantrine showed treatment failures with a single dose but cures with two doses, one of 1000 mg and one of 500 mg. A regimen of 500 mg at 6-hourly intervals was also effective. Three doses of 500 mg at 6-hourly intervals were also used in... 

Halofantrine is not indicated for prophylactic use. However, of 480 army personnel who took two doses of 1500 mg each on the third and the tenth days after they had returned to a non-malarial area, only one had P. falciparum malaria during the next 5 months (SEDA-13, 820) (1). There were no adverse effects, except for one case of morbilliform rash possibly due to the halofantrine. 

Adverse effects with the dosages originally recommended have in general been mild, no more than nausea, diarrhea, headache, and pruritus (SEDA-13, 820) (2-4). Pruritus occurred markedly less often with halofantrine than with chloroquine (SEDA-16, 306). A comparison between high-dose chloroquine (35 mg/kg total in three daily doses) and halofantrine in the standard dose (total 25 mg/kg given at 6-hour intervals) in patients 4—14 years old showed a fairly similar frequency of adverse effects. Itching was a common adverse effect of chloroquine (4). 

African children who received halofantrine (three doses of 8 mg/kg 6-hourly) for uncomplicated P. falciparum malaria had increases in both the PR interval and the QTc interval out of 42 children in the study, two children developed first-degree heart block and one child second-degree heart block the QT interval either increased by more than 125% of baseline value or by more than 0.44 seconds (an effect that persisted for at least 48 hours) (6). 

Prolongation of the QT interval occurred in 10 of 25 children treated with halofantrine (24 mg/kg oral suspension in three divided doses) for acute falciparum malaria (10). 

Wildling E, Jenne L, Graninger W, Bienzle U, Kremsner PG. High dose chloroquine versus micronized halofantrine in chloroquine-resistant Plasmodium falciparum malaria. J Antimicrob Chemother 1994 33(4) 871-5. 

Lumefantrine is a synthetic aminoalcohol fluorene derivative, related to halofantrine and mefloquine (1). It was highly effective in uncomplicated chloroquine-resistant malaria tropica in an open, non-comparative trial in 102 patients in China when given in four oral doses over 48 hours (2). No significant adverse effects have been reported. It has also been marketed in a combination of artemether (20 mg) plus lumefantrine (120 mg). 

Halofantrine is a potent blood schizontocidal agent with high activity against chloroquine-resistant and chloroquine-sensitive P, falciparum. The drug has been used at a dose of Ig/adult given daily for 3 days no phototoxicity or gastrointestinal problems were observed [138,139],... 

Magnesium carbonate 1 g reduced the maximum plasma levels of halofantrine 500 mg by almost 50% in a single-dose study in healthy subjeets. The AUC was also redueed by 28%, but this was not statistically significant. The aetive metabolite of halofantrine, which is equally potent, was similarly affeeted. ... 

A study in 6 healthy subjects found that the maximum plasma levels and AUC of a single 250-mg dose of halofantrine were increased by about 6.6-fold and 2.9-fold, respectively, when given with a fatty meal rather than in a fasting state. The AUC of the metabolite desbutylhalofantrine was also increased. Animal data suggest that fats may reduce the presystemic metabolism of halofantrine. As this is likely to increase the risk of halofantrine-induced arrhythmias, halofantrine should not be taken with meals, but should be taken on an empty stomach. 

A study in 8 healthy subjects found that tetracycline 500 mg twice daily for 7 days increased the maximum plasma levels, AUC and elimination half-life of a single 500-mg dose of halofantrine by 146%, 99%, and 73%, respectively. Increases in the major metabolite of halofantrine also occurred in the presence of tetracycline. As both halofantrine and tetracycline are excreted into the bile, competition for this elimination route may result in increased plasma levels. There may be an increased risk of halofantrine toxicity if it is used with higher doses of tetracycline. In contrast, in vitro studies found that doxycycline does not inhibit the metabolism of halofantrine. ... 

Milton K, Edwards G, Ward SA, Orme ML E, Breckenridge AM. Pharmacokinetics of halofantrine in man effects of food and dose size. BrJ Clin Pharmacol (1989) 28, 71-7. 

Hombhanje FW. Effect of a single dose of Fansidar on the pharmacokinetics of halofantrine in healdiy volunteers a preliminary report. BrJ Clin Pharmacol (2000) 49, 283. ... 

Halofantrine Quinine (greater risk with higher doses and intravenous use)... 

---