Ethionamide

Ethionamide is bacteriostatic against M. tuberculosis at therapeutic concentrations, but may be bactericidal at higher concentrations. Ethionamide is also active against M. kansasii, M. leprae and some strains of M. avium-complex. The exact mechanism of action of ethionamide has not been fully elucidated, but the drug appears to inhibit peptide synthesis in susceptible organisms. Drug resistance develops rapidly when ethionamide is given as monotherapy.

Absorption

Ethionamide is nearly completely absorbed upon oral administration.

Following single dose administration of ethionamide 125 mg dispersible tablets in healthy volunteers, the mean (± SD) ethionamide C_max value was 3.584 μg/ml (± 1.002), the corresponding value for AUC_0-t was 9.121 μg.h/ml (± 2.005) and the mean (± SD) ethionamide t_max value was 0.46 (± 0.17) hours.

Distribution and elimination

Plasma protein binding is approximately 30%, and the volume of distribution has been reported to be approximately 80 liters. Ethionamide undergoes extensive hepatic metabolism into several different metabolites, with only approximately 1% of a given dose excreted unchanged in the urine. Ethionamide-sulfoxide is the major metabolite; it has been reported to have antibacterial activity. The plasma half-life of ethionamide is approximately 2-3 hours.

Special populations

Renal/hepatic impairment

Pharmacokinetic data are available neither for patients with renal impairment nor for patients with mild to moderate hepatic impairment.

Children

Data on the pharmacokinetics of ethionamide in paediatric patients are scarce. One study in children aged 0-12 years showed that a daily dose of 15-20 mg/kg yielded C_max values above a target concentration of 2.5µg/ml in the majority of patients. This target concentration was based on published expert opinion. Exposures tended to be lower in younger patients, particularly in those <2 years of age.

Carcinogenic effects

A bioassay for possible carcinogenicity was conducted by administering ethionamide in feed to Fischer 344 rats and B6C3F1 mice. Groups of 35 rats and 34 or 35 mice of each sex were administered ethionamide at either 1,500 or 3,000 ppm for the rats, and either 1,000 or 2,000 ppm for the mice. It is concluded that under the conditions of this bioassay, ethionamide was not carcinogenic in either Fischer 344 rats or B6C3F1 mice.

Teratogenic effects

Animal studies conducted with ethionamide indicate that the drug has a teratogenic potential in rabbits and rats. The doses used in these studies on a mg/kg basis were considerably in excess of those recommended in humans. There are no adequate and well-controlled studies in pregnant women.

Mutagenic effects

Ethionamide was not found to be mutagenic, as shown by Ames Salmonella & micronuclei Assay Test.