Chemical formula: C₁₈H₃₇N₅O₉ Molecular mass: 467.515 g/mol PubChem compound: 36294
Tobramycin is an aminoglycoside antibiotic produced by Streptomyces tenebrarius. It acts primarily by disrupting protein synthesis leading to altered cell membrane permeability, progressive disruption of the cell envelope and eventual cell death. It is bactericidal at concentrations equal to or slightly greater than inhibitory concentrations.
Established susceptibility breakpoints for parenteral administration of tobramycin are inappropriate in the aerosolised administration of the medicinal product.
Sputum from cystic fibrosis exhibits an inhibitory action on the local biological activity of inhaled aminoglycosides. This necessitates sputum concentrations of tobramycin after inhalation to be about ten-fold above the minimum inhibitory concentration (MIC) or higher for P. aeruginosa suppression. In the active-controlled study, at least 89% of patients had P. aeruginosa isolates with MICs at least 15 times lower than mean post-dose sputum concentration, both at baseline and at the end of the third active treatment cycle.
In the absence of conventional susceptibility breakpoints for the inhaled route of administration, caution must be exercised in defining organisms as susceptible or insusceptible to inhaled tobramycin.
The clinical significance of changes in MICs of tobramycin for P. aeruginosa has not been clearly established in the treatment of cystic fibrosis patients. Clinical studies with inhaled tobramycin solution have shown a small increase in tobramycin, amikacin and gentamicin Minimum Inhibitory Concentrations for P. aeruginosa isolates tested. In the open label extensions, each additional 6 months of treatment resulted in incremental increases similar in magnitude to that observed in the 6 months of placebo-controlled studies.
Resistance to tobramycin involves different mechanisms. The main resistance mechanisms are drug efflux and drug inactivation by modifying enzymes. The unique characteristics of chronic P. aeruginosa infections in CF patients, such as anaerobic conditions and high frequency of genetic mutations, may also be important factors for reduced susceptibility of P. aeruginosa in CF patients.
Based upon in vitro data and/or clinical trial experience, the organisms associated with pulmonary infections in CF may be expected to respond to tobramycin inhalation powder therapy as follows:
Susceptible: Pseudomonas aeruginosa, Haemophilus influenzae, Staphylococcus aureus
Insusceptible: Burkholderia cepacia, Stenotrophomonas maltophilia, Alcaligenes xylosoxidans
Following intramuscular administration of a single dose of tobramycin 1 mg/kg in adults with normal renal function, peak plasma tobramycin concentrations averaging 4-6 micrograms/ml are obtained within 30-90 minutes; plasma concentrations of the drug are 1 microgram/ml or less at 8 hours. Following intravenous infusion of the same dose over 30-60 minutes, similar plasma concentrations of the drug are obtained. Tobramycin is poorly absorbed from the gastrointestinal tract.
The systemic exposure to tobramycin after inhalation is expected to be primarily from the inhaled portion of the medicinal product as tobramycin is not absorbed to any appreciable extent when administered via the oral route.
After injection tobramycin has been detected in body fluids but concentrations in the cerebrospinal fluid are low even when there is meningeal inflammation. Most bodily compartments and tissues including the inner ear and kidneys become progressively saturated with aminoglycosides over the course of therapy, and the drug is slowly released from these areas. It has been postulated that this accumulation may account for the ototoxicity and nephrotoxicity associated with aminoglycosides. In general, aminoglycosides such as tobramycin readily cross the placenta. Small amounts of the drugs are also distributed into bile, saliva, sweat, tears, sputum, and milk.
A population pharmacokinetic analysis for tobramycin inhalation powder in cystic fibrosis patients estimated the apparent volume of distribution of tobramycin in the central compartment to be 84.1 litres for a typical CF patient. While the volume was shown to vary with body mass index (BMI) and lung function (as FEV1% predicted), model-based simulations showed that peak (Cmax) and trough (Ctrough) concentrations were not impacted markedly with changes in BMI or lung function.
Tobramycin is not metabolised and is primarily excreted unchanged in the urine.
The major route of elimination is renal and the drug is eliminated almost entirely by glomerular filtration. Protein binding of tobramycin has been reported as zero. The plasma elimination half-life of tobramycin is usually 2-3 hours in adults with normal renal function and is reported to range from 5 to 70 hours in adults with impaired renal function. In full- term infants the plasma elimination half-life is reported to average 4.6 hours and in low birth-weight infants it averages 8.7 hours.
Peak urine concentrations ranging from 75 to 100 microgram/ml have been observed after the intramuscular injection of a single dose of 1 mg/kg. After several days of treatment, the amount of tobramycin excreted in the urine approaches the daily amount administered. When renal function is impaired, excretion of tobramycin is slowed, and accumulation of the drug may cause toxic blood levels. In patients undergoing dialysis, 25 to 70% of the administered dose may be removed, depending on the duration and type of dialysis.
Tobramycin is eliminated from the systemic circulation primarily by glomerular filtration of the unchanged compound. The apparent terminal half-life of tobramycin in serum after inhalation of a 112 mg single dose of tobramycin inhalation powder was approximately 3 hours in cystic fibrosis patients and consistent with the half-life of tobramycin after inhalation of tobramycin 300 mg/5 ml nebuliser solution.
A population pharmacokinetic analysis for tobramycin inhalation powder in cystic fibrosis patients aged 6 to 66 years estimated the apparent serum clearance of tobramycin to be 14 litres/h. This analysis did not show gender or age-related pharmacokinetic differences.
Non-clinical data reveal that the main hazard for humans, based on studies of safety pharmacology, repeated dose toxicity, genotoxicity, or toxicity to reproduction, consists of renal toxicity and ototoxicity. In general, toxicity is seen at higher systemic tobramycin levels than are achievable by inhalation at the recommended clinical dose.
Carcinogenicity studies with inhaled tobramycin do not increase the incidence of any variety of tumour. Tobramycin showed no genotoxic potential in a battery of genotoxicity tests.
No reproduction toxicology studies have been conducted with tobramycin administered by inhalation. However, subcutaneous administration of tobramycin during organogenesis was not teratogenic nor embryotoxic. Severely maternally toxic doses to female rabbits (i.e. nephrotoxicity) lead to spontaneous abortions and death. Based on available data from animals a risk of toxicity (e.g. ototoxicity) at prenatal exposure levels cannot be excluded.
Subcutaneous administration of tobramycin did not affect mating behaviour or cause impairment of fertility in male or female rats.
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