Source: Health Products and Food Branch (CA) Revision Year: 2019
Ethambutol is bacteriostatic in action. Although the exact mechanism of action has not been fully elucidated, the drug appears to inhibit the synthesis of one or more metabolites in susceptible bacteria resulting in impairment of cellular metabolism, arrest of multiplication, and cell death. Ethambutol is active against susceptible bacteria only when they are undergoing cell division.
Ethambutol is a highly specific agent and is active only against organisms of the genus Mycobacterium. The drug is active in vitro and in vivo against M. tuberculosis, M. bovis, M. marinum, and some strains of M. kansasii, M. avium, M. fortuitum, and M. intracellulare. In vitro, the minimum inhibitory concentration (MIC) of ethambutol for most susceptible mycobacteria is 1 to 8 mcg/mL, depending on the culture media used.
Natural and acquired resistance to ethambutol have been demonstrated in vitro and in vivo in strains of M. tuberculosis. In vitro, resistance to ethambutol appears to occur in a stepwise manner. Resistant strains of initially susceptible M. tuberculosis develop rapidly if ethambutol is used alone in the treatment of clinical tuberculosis. When ethambutol is combined with other antituberculosis agents in the treatment of the disease, emergence of resistant strains may be delayed or prevented. There is no evidence of cross-resistance between ethambutol and other antituberculosis agents currently available on the market.
Approximately 75 to 80% of an oral dose of ethambutol is rapidly absorbed from the GI tract. Absorption is not substantially affected when the drug is administered with food. Following a single oral dose of 25 mg/kg, peak serum ethambutol concentrations of 2 to 5 mcg/mL are attained within 2 to 4 hours; serum concentrations of the drug are undetectable 24 hours after the dose. There is no evidence that accumulation of the drug occurs when ethambutol doses of 25 mg/kg are given once daily in patients with normal renal function. Serum concentrations of the drug are higher and accumulation may occur when ethambutol is used in patients with impaired renal function.
Ethambutol is widely distributed into most body tissues and fluids. Highest concentrations of the drug are found in erythrocytes, kidneys, lungs, and saliva; lower drug concentrations are found in ascitic fluid, pleural fluid, brain, and CSF. Peak intracellular concentrations of ethambutol in erythrocytes are about twice peak plasma concentrations and maintain this ratio for at least 24 hours after a single oral dose. In patients with meningitis, administration of an oral ethambutol dose of 25 mg/kg has produced peak CSF concentrations of the drug ranging from 0.15 to 2.0 mcg/mL.
Ethambutol crosses the placenta and is distributed into cord blood and amniotic fluid. Ethambutol is distributed into milk in concentrations approximately equal to plasma concentrations of the drug. Plasma protein binding of ethambutol is low and ranges between 20 and 30%.
The plasma half-life of ethambutol is approximately 3.3 hours in patients with normal renal function. The half-life is prolonged in patients with impaired renal or hepatic function. In patients with renal failure, the half-life may be 7 hours or longer.
Ethambutol is excreted renal by glomerular filtration and tubular secretion. Up to 80% of the dose is excreted within 24 hours (at least 50% excreted unchanged and up to 15% as inactive metabolite). Twenty (20%) per cent of the dose is excreted unchanged in feces. Ethambutol can be removed from the blood by hemodialysis and peritoneal dialysis.
A single 25 mg/kg dose of ETIBI (ethambutol) was administered to each of twenty (20) human volunteers, and plasma concentration and urinary recovery rate determinations were performed. In 12 subjects the average highest plasma level, 5.18 mcg/mL, was seen two hours after drug ingestion, while in the other 8, the highest concentration was seen at four hours. The peak plasma level may thus be expected to occur between one and four hours following drug ingestion. Recovery of ethambutol from urines of the test group showed a urinary recovery rate of 46.68% in 24 hours. These results are in good agreement with published data on absorption and excretion.
In vitro tests were carried out on 100 strains of M. tuberculosis isolated from patients previously not treated with ETIBI, and on 20 strains isolated from patients unsuccessfully treated.
In these studies, ethambutol was incorporated in Löwenstin-Jensen media in concentrations of 1, 2, and 3 mcg/mL. The previously untreated strains were inhibited to a large extent by 1 mcg/mL. On media containing 2 mcg /mL ethambutol, complete inhibition was observed in 78 strains and, in the remaining strains, the rate of inhibition was 95% or more. At the level of 3 mcg/mL, all strains were inhibited.
In contrast, strains isolated from patients unsuccessfully treated with ethambutol were not inhibited satisfactorily at any dose level.
From in vivo studies using 15 patients, a bacteriostatic concentration is maintained for at least 6 hours at a dose level of 25 mg/kg given orally. The observed concentration started at 6.86 mcg/mL in the first 2 hours decreasing to 1.61 mcg/mL at 8 hours.
Two species were used to determine the Acute Oral Toxicity of ETIBI. In albino mice, a test dose of 10,000 mg/kg did not cause immediate or delayed mortality in animals of either sex. At this high dose level, most mice appeared slightly ataxic, but at post mortem examination, no significant gross pathological changes were found. In a second experiment using beagle dogs, dose levels of from 300 mg/kg to 2,000 mg/kg of body weight were administered without ensuing mortality. Due to the mechanical difficulties of administering larger doses the experiment was terminated. The acute oral toxicity of ETIBI was thus determined to be greater than 2,000 mg/kg. Significant signs of acute intoxication with ETIBI at 2 g/kg were not detected.
The Chronic Oral Toxicity of ETIBI was the subject of a twelve-month study in the beagle dog. Daily dose levels of 25 mg/kg, 100 mg/kg, and 400 mg/kg were evaluated. Survival was 100% but hind limb stiffness and mild ataxia were observed in all animals at the highest dose level. Results of blood chemistry studies indicated a drug related effect on the liver of all dosage levels. The most consistent of these changes was a slight increase in the level of SGPT (ALT) although increased values for alkaline phosphatase were occasionally recorded together with evidence of a mild degree of bromsulfophthalein retention.
Hemograms were obtained for all animals prior to and following 1, 2, 6, and 12 months of drug treatment. The following parameters were evaluated: total and differential leucocyte counts, prothrombin time, clotting time, RBC count, hemoglobin concentration, hematocrit, mean corpuscular volume, sedimentation rate, and platelet count.
Hematologic changes included marginal depressed values for hemoglobin, hematocrit and RBC count after one month of treatment in one dog. Transient leucocytosis was observed in two animals and several had unusual low WBC counts after 6 and 12 months of treatment.
Ocular examinations revealed complete depigmentation of the tapetum lucidum of each animal at the 400 mg/kg level and partial depigmentation at the 100 mg/kg level. Cardia hypertrophy discovered at autopsy was a prominent finding but no electrocardiographic or histopathologic changes were observed. A study of fetal toxicity was carried out in Sprague-Dawley albino rats and New Zealand rabbits. Ethambutol was administered subcutaneously in three dose levels, 0, 50, and 100 mg/kg.
In the rat, ethambutol produced fetal malformation of 1.87% at the level of 100 mg/kg. However, no significant changes were observed on fertility and reproduction.
In the rabbit the 100 mg/kg dose level produced a mortality of 50% in the dams, caused by hepatic and renal damage. Malformations were not observed at any dose level, however, resorption and fetal toxicity were evident at both 50 and 100 mg/kg.
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