CLINICAL PHARMACOLOGY
TOBI® is specifically formulated for administration by inhalation. When inhaled, tobramycin is concentrated in the airways.
Pharmacokinetics
TOBI® contains tobramycin, a cationic polar molecule that does not readily cross epithelial membranes.(1) The bioavailability of TOBI® may vary because of individual differences in nebulizer performance and airway pathology.(2) Following administration of TOBI®, tobramycin remains concentrated primarily in the airways.
Sputum Concentrations : Ten minutes after inhalation of the first 300-mg dose of TOBI®, the average concentration of tobramycin was 1237 µg/g (ranging from 35 to 7414 µg/g) in sputum. Tobramycin does not accumulate in sputum; after 20 weeks of therapy with the TOBI® regimen, the average concentration of tobramycin at ten minutes after inhalation was 1154 µg/g (ranging from 39 to 8085 µg/g) in sputum. High variability of tobramycin concentration in sputum was observed. Two hours after inhalation, sputum concentrations declined to approximately 14% of tobramycin levels at ten minutes after inhalation.
Serum Concentrations: The average serum concentration of tobramycin one hour after inhalation of a single 300-mg dose of TOBI® by cystic fibrosis patients was 0.95 µg/mL. After 20 weeks of therapy on the TOBI® regimen, the average serum tobramycin concentration one hour after dosing was 1.05 µg/mL.
Elimination: The elimination half-life of tobramycin from serum is approximately 2 hours after intravenous (IV) administration. Assuming tobramycin absorbed following inhalation behaves similarly to tobramycin following IV administration, systemically absorbed tobramycin is eliminated principally by glomerular filtration. Unabsorbed tobramycin, following TOBI® administration, is probably eliminated primarily in expectorated sputum.
Microbiology
Tobramycin is an aminoglycoside antibiotic produced by Streptomyces tenebrarius.(1) It acts primarily by disrupting protein synthesis, leading to altered cell membrane permeability, progressive disruption of the cell envelope, and eventual cell death.(3)
Tobramycin has in-vitro activity against a wide range of gram-negative organisms including Pseudomonas aeruginosa. It is bactericidal at concentrations equal to or slightly greater than inhibitory concentrations.
Susceptibility Testing
A single sputum sample from a cystic fibrosis patient may contain multiple morphotypes of Pseudomonas aeruginosa and each morphotype may have a different level of in-vitro susceptibility to tobramycin. Treatment for 6 months with TOBI® in two clinical studies did not affect the susceptibility of the majority of P. aeruginosa isolates tested; however, increased minimum inhibitory concentrations (MICs) were noted in some patients. The clinical significance of this information has not been clearly established in the treatment of P. aeruginosa in cystic fibrosis patients. For additional information regarding the effects of TOBI® on P. aeruginosa MIC values and bacterial sputum density, please refer to the CLINICAL STUDIES section.
The in-vitro antimicrobial susceptibility test methods used for parenteral tobramycin therapy can be used to monitor the susceptibility of P. aeruginosa isolated from cystic fibrosis patients. If decreased susceptibility is noted, the results should be reported to the clinician.
Susceptibility breakpoints established for parenteral administration of tobramycin do not apply to aerosolized administration of TOBI®. The relationship between in-vitro susceptibility test results and clinical outcome with TOBI® therapy is not clear.
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