Bifonazole

Bifonazole exerts its anti-fungal action by inhibiting the biosynthesis of ergosterol on two different levels. Inhibition of ergosterol synthesis leads to structural and functional impairment of the cytoplasmic membrane.

Bifonazole is an imidazole derivative with a broad antimycotic spectrum, which includes dermatophytes, yeasts, moulds and other fungi such as Malassezia furfur. It is also effective against Corynebacterium minutissimum.

The resistance situation for bifonazole is favourable. Primary resistant variants of sensitive fungal species are very rare. Investigations so far did not provide any evidence of a development of secondary resistance in primarily sensitive strains.

Absorption

Bifonazole penetrates well into infected skin layers. 6 hours after administration concentrations in the various skin layers reach from 1000 μg/cm³ in the top layer of the epidermis (stratum corneum) to 5 μg/cm³ in the stratum papillare. All concentrations determined are thus within a range of reliable antimycotic activity.

After a single application (topical) of 15.2mg [¹⁴C] bifonazole cream, and subsequent occlusion for six hours, 0.6±0.3% of the dose was absorbed. The absorption rate was approximately 0.008mg/100cm² per hour. In inflamed skin these values were higher by a factor of four. Similar results were obtained after the application of bifonazole as a 1% solution.

Plasma levels up to 16ng/ml were obtained in babies with nappy rash after a single 5g application of the cream.

After intravenous administration of 0.016mg/kg [¹⁴C] bifonazole, tissue uptake was rapid. Bifonazole is, however, rapidly metabolised with only 30% of an intravenous dose remaining unaltered 30 minutes post-dose.

Elimination

Elimination of the metabolites is biphasic (T½ of eight and 50 hours). Within five days of administration 45% of the administered dose has been excreted renally, with 40% being eliminated via the liver and bile (faeces).

Toxicological studies showed good local tolerability of topical formulations. With bifonazole cream and solution slight skin irritant effects were observed which could be attributed to the excipients 2-octyldodecanol (cream) and isopropyl myristate (solution), respectively. There were no indications of changes caused specifically by the active substance, and no signs of any systemic effects were observed.

Preclinical data on oral dosage forms reveal no special hazards for humans based on conventional studies of single dose toxicity and genotoxicity. Effects on the liver (enzyme induction, fatty degeneration) were observed in repeated dose toxicity studies with oral administration but only at exposures in excess of the maximum human exposure indicating little relevance to clinical use. No carcinogenicity studies were performed with bifonazole.

In reproduction toxicology studies in rats and rabbits, oral doses of 30 mg/kg body weight resulted in embryotoxicity including lethality. In the rats, bifonazole at oral doses up to 100 mg/kg body weight was not embryotoxic, but a retarded skeletal development in the fetuses was observed at the dose of 100 mg/kg. This fetal effect on the skeletal development can be considered as a secondary effect resulting from the maternal toxicity (a reduction in body weight).

Given the low absorption of the active ingredient via the skin these results have little relevance to clinical use. In a study of lactating rats treated with radioactively labelled bifonazole (10 mg/kg body weight intravenous), approximately 3.2% of the dose was excreted in the milk. In another study of radioactively labelled bifonazole, it was found that intravenously administered bifonazole (10mg/kg body weight) passes through the placental barrier in rats.

No impairment of male or female fertility was observed in rats at oral doses up to 40 mg/kg body weight.