Karbwang J, Na Bangchang K
Department of Clinical Tropical Medicine and Hospital for Tropical Diseases, Bangkok, Thailand.
Clin Pharmacokinet. 1994 Aug;27(2):104-19. doi: 10.2165/00003088-199427020-00003.
Halofantrine is a phenanthrenemethanol antimalarial that is effective against asexual forms of multidrug-resistant Plasmodium falciparum malaria. It has no action on gametocytes or hypnozoites in the liver. The drug is administered as a racemic mixture but the (+)- and (-)-enantiomers show no difference in activity in vitro. Three formulations for oral administration are available for human use, i.e. tablets, capsules and suspension. Toxicity studies in animals suggest that halofantrine has very low toxicity both in short term and long term animal studies, and there has been no evidence of mutagenicity in these studies. Phase I, II and III clinical trials of halofantrine conducted in several tropical countries found the drug to be well tolerated and effective against multidrug-resistant P. falciparum malaria when 500mg was administered every 6 hours for 3 doses. The majority of clinical adverse effects reported, including nausea, vomiting, abdominal pain, diarrhoea, orthostatic hypotension, prolongation of QTc interval, pruritus and rash, have been mild and transient. There is wide interindividual variation in halofantrine absorption. The maximal plasma concentration (Cmax) is achieved approximately 6 hours after oral administration. Bioavailability is not dose-proportional for doses over 500mg, but there is a dose-proportional increase in Cmax and area under the plasma concentration-time curve (AUC) for doses between 250 and 500mg. In patients with malaria the bioavailability of halofantrine is decreased. The mean half-life of absorption is 4 hours and Cmax is significantly lower than that obtained in healthy individuals. Furthermore, halofantrine absorption is enhanced when the drug is taken with fatty food. Therefore, halofantrine should be taken with food to ensure optimal absorption in patients with malaria. The terminal elimination half-life is 5 days in patients with malaria. Halofantrine is biotransformed in the liver to its major metabolite N-debutyl-halofantrine. Plasma concentrations of this metabolite are observed soon after administration of halofantrine, but in much lower concentrations. The elimination half-life is similar to that of halofantrine. There have been increasing reports of halofantrine treatment failure, particularly in the eastern part of Thailand. The majority of treatment failures have been associated with incomplete drug absorption. The dose-dependent cardiotoxic effects (e.g. cardiac arrhythmia) are a major concern, particularly when the bioavailability of the drug cannot be predicted. Ongoing and future studies should aim at developing more appropriate drug formulation(s) and/or optimising dosage regimens. This will allow therapeutic concentrations to be achieved with minimum adverse effects, particularly cardiotoxicity.
卤泛群是一种菲甲醇类抗疟药，对多重耐药恶性疟原虫的无性体有效。它对配子体或肝脏中的休眠子无作用。该药物以消旋混合物形式给药，但（+）-和（-）-对映体在体外活性上无差异。有三种口服制剂可供人类使用，即片剂、胶囊和混悬液。动物毒性研究表明，在短期和长期动物研究中卤泛群的毒性都非常低，并且在这些研究中没有致突变性的证据。在几个热带国家进行的卤泛群I期、II期和III期临床试验发现，当每6小时服用500mg，共服用3剂时，该药物耐受性良好，对多重耐药恶性疟有效。报告的大多数临床不良反应，包括恶心、呕吐、腹痛、腹泻、体位性低血压、QTc间期延长、瘙痒和皮疹，都很轻微且短暂。卤泛群的吸收存在很大的个体差异。口服给药后约6小时达到最大血浆浓度（Cmax）。对于超过500mg的剂量，生物利用度与剂量不成比例，但对于250至500mg的剂量，Cmax和血浆浓度-时间曲线下面积（AUC）呈剂量依赖性增加。在疟疾患者中，卤泛群的生物利用度降低。平均吸收半衰期为4小时，Cmax显著低于健康个体。此外，与脂肪类食物一起服用时卤泛群的吸收会增强。因此，卤泛群应与食物一起服用，以确保疟疾患者达到最佳吸收。疟疾患者的终末消除半衰期为5天。卤泛群在肝脏中生物转化为其主要代谢产物N-去丁基卤泛群。服用卤泛群后很快就能观察到该代谢产物的血浆浓度，但浓度要低得多。消除半衰期与卤泛群相似。越来越多的报告称卤泛群治疗失败，尤其是在泰国东部。大多数治疗失败与药物吸收不完全有关。剂量依赖性心脏毒性作用（如心律失常）是一个主要问题，尤其是当药物的生物利用度无法预测时。正在进行的和未来的研究应致力于开发更合适的药物制剂和/或优化给药方案。这将使治疗浓度在产生最小不良反应（尤其是心脏毒性）的情况下得以实现。
