Chemical formula: C₁₉H₁₉NOS Molecular mass: 309.425 g/mol PubChem compound: 3827
Ketotifen is a non-bronchodilator, anti-asthmatic drug which inhibits the effect of certain endogenous substances known to be inflammatory mediators, and thereby exerts anti-allergic activity.
Laboratory experiments indicate that this anti-anaphylactic activity may be due to the inhibition of release of allergic mediators such as histamine and leukotrienes. The suppression of the priming of eosinophils by human recombinant cytokines and thereby suppression of the influx of eosinophils into inflammatory loci and the inhibition of the development of airway hyperactivity associated with activation of platelets by PAF (platelet activating factor) or caused by neural activation following the use of sympathomimetic drugs or the exposure to allergen. In addition, ketotifen exerts a non-competitive blocking effect on histamine (H1) receptors. Therefore, it can also be used in place of classical histamine (H1) receptor antagonists. Ketotifen is an established product. There are no new clinical studies.
After oral administration, the absorption of ketotifen is almost complete. Bioavailability amounts to approximately 50% owing to a first-pass effect of about 50% in the liver. Maximal plasma concentrations are reached within 2 to 4 hours.
Protein binding is 75%.
The main metabolite is ketotifen-N-glucuronide. This is practically inactive.
Ketotifen is eliminated biphasically, with a short half-life of 3 of 5 hours and a longer one of 21 hours. About 1% of the substance is excreted unchanged in the urine within 48 hours and 60 to 70% is excreted as metabolites.
The bioavailability of ketotifen is not influenced by food. Therefore ketotifen can be taken with or without food. However, smooth plasma concentration profile may be observed when administered with meals.
The pattern of metabolism in children is the same as in adults, but the clearance is higher in children below 3 years. Therefore, the ketotifen dose per kilogram is higher for children compared to the adults. Children over the age of 3 years therefore require the same daily dose regimen as adults.
No relevant pharmacokinetic studies have been performed with ketotifen in patients with hepatic impairment. Since ketotifen is metabolized in the liver and its glucuronidation may be impaired in severe hepatic impairment, the clearance of ketotifen will most likely be reduced in patients with severe hepatic impairment and the possibility of accumulation of unchanged drug cannot be excluded.
No relevant pharmacokinetic studies have been performed with ketotifen in patients with renal impairment. However, considering that 60-70% of the dose is excreted in urine as metabolites, an increased risk of adverse reactions due to accumulation of metabolites cannot be excluded.
In a pharmacokinetic study conducted in 18 healthy volunteers with ketotifen eye drops, plasma levels of ketotifen after repeated ocular administration for 14 days were in most cases below the limit of quantitation (20pg/ml).
After oral administration, ketotifen is eliminated biphasically with an initial half-life of 3 to 5 hours and a terminal half-life of 21 hours. About 1% of the substance is excreted unchanged in the urine within 48 hours and 60 to 70% as metabolites. The main metabolite is the practically inactive ketotifen-N-glucuronide.
Acute toxicity studies of ketotifen in mice, rats and rabbits revealed oral LD50 values above 300mg/kg bodyweight and between 5 and 20mg/kg by the iv route. Adverse effects induced by overdose were dyspnoea and motor excitation followed by spasms and drowsiness. Toxic signs appeared rapidly and disappeared within hours; there was no evidence of cumulative or delayed effects. Other studies yielded an oral LD50 value of ketotifen in rats of 161mg/kg and demonstrated that the toxicity of ketotifen syrup (LD50 31.1mg/kg) was attributable to the sorbitol excipient alone. A total daily dose of 10 ml administered to a child of 30kg would be equivalent to 0.33ml/kg ketotifen syrup and 0.07mg/kg ketotifen base, indicating a sufficiently wide safety margin.
No evidence of skin sensitizing potential of ketotifen was obtained in guinea pigs by intracutaneous injection.
Ketotifen and/or its metabolites were devoid of genotoxic potential, when investigated in vitro for induction of gene mutation in Salmonella typhimurium, for chromosome aberrations in V79 Chinese hamster cells, or for primary DNA damage in rat hepatocyte cultures. No clastogenic activity was observed in vivo (cytogenic analysis of bone marrow cells in the Chinese hamster, bone marrow micronucleus assay in mice). Likewise, no mutagenic effects were evident on the germ cells of male mice in the dominant lethal test.
In rats treated continuously in the diet for 24 months, maximum tolerated doses of 71mg/kg ketotifen per day revealed no carcinogenic potential. No evidence of tumorigenic effects was obtained in mice treated with up to 88mg/kg body weight in the diet for 74 weeks.
No embryotoxic or teratogenic potential of ketotifen was revealed in rats or rabbits. In male rats treated for 10 weeks (i.e. more than a complete spermatogenic cycle) before mating, fertility was unaffected at a tolerated dose of 10mg/kg per day.
The fertility of female rats as well as prenatal development, pregnancy and weaning of the offspring were not adversely affected by ketotifen treatment at oral dose levels of up to 50mg/kg per day, although non-specific toxicity to the pregnant females was observed at and above 10mg/kg. Likewise, no adverse effect of treatment was found in the peri-natal phase. Due to the maternal toxicity, some decrease in pup survival and weight gain was recorded during the first days of post-natal development at the high dose level of 50mg/kg per day.
Preclinical data reveal no special hazard which is considered relevant in connection with use of ketotifen eye drops in humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential and toxicity to reproduction.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
