Trecator Pharmacology, Pharmacokinetics, Studies, Metabolism - Ethionamide

Trecator Pharmacology, Pharmacokinetics, Studies, Metabolism - Ethionamide

CLINICAL PHARMACOLOGY

Ethionamide is essentially completely absorbed following oral administration and is not subjected to any appreciable first pass metabolism. ¹ Following a single 250 mg oral dose of ethionamide in healthy volunteers, peak plasma concentrations of about 2 µg/mL were attained at 2 hours in most cases. Normal serum concentrations of 1 to 5 µg/mL are usually seen 2 hours following doses of 250 mg to 500 mg. ² These concentrations approximate the therapeutic range for this drug when the therapeutic range is defined by those serum concentrations associated with a high probability of success and a low probability of dose-related toxicity. The drug is approximately 30 percent bound to plasma proteins. Trecator-SC is rapidly and widely distributed into body tissues and fluids, with concentrations in plasma and various organs being approximately equal. Significant concentrations also are present in cerebrospinal fluid.

Ethionamide is extensively metabolized to active and inactive metabolites with less than 1% excreted as the free form in urine. Metabolism is presumed to occur in the liver and thus far 6 metabolites have been isolated: 2-ethylisonicotinamide, carbamoyl-dihydropyridine, thiocarbamoyl-dihydropyridine, S-oxocarbamoyl dihydropyridine, 2-ethylthioiso-nicotinamide, and ethionamide sulphoxide. The sulphoxide metabolite has been demonstrated to have antimicrobial activity against Mycobacterium tuberculosis . Trecator-SC has a plasma elimination half-life of approximately 2 hours after oral dosing.

Mechanism of Action

Ethionamide may be bacteriostatic or bactericidal in action, depending on the concentration of the drug attained at the site of infection and the susceptibility of the infecting organism. The exact mechanism of action of ethionamide has not been full elucidated, but the drug appears to inhibit peptide synthesis in susceptible organisms.

Microbiology

In Vitro Activity

Ethionamide exhibits bacteriostatic activity against extracellular and intracellular Mycobacterium tuberculosis organisms. The development of ethionamide resistant M. tuberculosis isolates can be obtained by repeated subculturing in liquid or on solid media containing increasing concentrations of ethionamide. Multi-drug resistant strains of M. tuberculosis may have acquired resistance to both isoniazid and ethionamide. However, the majority of M. tuberculosis isolates that are resistant to one are usually susceptible to the other. There is no evidence of cross-resistance between ethionamide and para-aminosalicylic acid (PAS), streptomycin, or cycloserine. However, limited data suggest that cross-resistance may exist between ethionamide and thiosemicarbazones (i.e., thiacetazone) as well as isoniazid.

In Vivo Activity

Ethionamide administered orally initially decreased the number of culturable Mycobacterium tuberculosis organisms from the lungs of H37Rv infected mice. Drug resistance developed with continued ethionamide monotherapy, but did not occur when mice received ethionamide in combination with streptomycin or isoniazid.

SUSCEPTIBILITY TESTING

Ethionamide susceptibility testing should only be performed by qualified or reference laboratories.

Two standardized in vitro susceptibility methods are available for testing ethionamide against M. tuberculosis organisms. The modified proportion method (CDC or NCCLS M24-P) utilizes Middlebrook and Cohn 7H10 agar medium impregnated with ethionamide at a final concentration of 5.0 µg/mL. After 2 to 3 weeks of incubation, MIC ₉₉ values are calculated by comparing the quantity of organisms growing in the medium containing drug to the control cultures. Mycobacterial growth in the presence of drug, of at least 1% of the growth in the control culture, indicates resistance.

The radiometric broth method employs the BACTEC 460 machine to compare the growth index from untreated control cultures to cultures grown in the presence of 5.0 µg/mL of ethionamide. Strict adherence to the manufacturer's instructions for sample processing and data interpretation is required for this assay.

Susceptibility test results obtained by these two different methods cannot be compared unless equivalent drug concentrations are evaluated.

The clinical relevance of in vitro susceptibility test results for mycobacterial species other than M. tuberculosis using either the radiometric or the proportion method has not been determined.