Sputum concentrations

After inhalation of a 112 mg single dose (4 x 28 mg capsules) of TOBI Podhaler in cystic fibrosis patients, sputum Cmax of tobramycin was 1048 ± 1080 µg/g (mean ± SD). In comparison, after inhalation of a single 300 mg dose of TOBI, sputum Cmax was 737 ± 1028 µg/g. The variability in pharmacokinetic parameters was higher in sputum as compared to serum.

Distribution

A population pharmacokinetic analysis for TOBI Podhaler in cystic fibrosis patients estimated the apparent volume of distribution of tobramycin in the central compartment to be 85.1 L for a typical CF patient.

Binding of tobramycin to serum proteins is negligible.

Metabolism

Tobramycin is not metabolized and is primarily excreted unchanged in the urine.

Elimination

Tobramycin is eliminated from the systemic circulation primarily by glomerular filtration of the unchanged compound. Systemically absorbed tobramycin following TOBI Podhaler administration is also expected to be eliminated principally by glomerular filtration.

The apparent terminal half-life of tobramycin in serum after inhalation of a 112 mg single dose of TOBI Podhaler was approximately 3 hours in cystic fibrosis patients and consistent with the half-life of tobramycin after TOBI inhalation.

A population pharmacokinetic analysis for TOBI Podhaler in cystic fibrosis patients aged 6 to 58 years estimated the apparent serum clearance of tobramycin to be 14.5 L/h. No clinically relevant covariates that were predictive of tobramycin clearance were identified from this analysis.

12.4 Microbiology
Mechanism of Action

Tobramycin is an aminoglycoside antimicrobial 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.

Tobramycin has in vitro activity against Gram-negative bacteria including P. aeruginosa. It is bactericidal in vitro at peak concentrations equal to or slightly greater than the minimum inhibitory concentration.

Susceptibility Testing

Interpretive criteria for inhaled antibacterial products are not defined. The in vitro antimicrobial susceptibility test methods used to determine the susceptibility for parenteral tobramycin therapy can be used to monitor the susceptibility of P. aeruginosa isolated from cystic fibrosis patients (1, 2, 3). The relationship between in vitro susceptibility test results and clinical outcome with TOBI Podhaler therapy is not clear. A single sputum sample from a cystic fibrosis patient may contain multiple morphotypes of P. aeruginosa and each morphotype may require a different concentration of tobramycin to inhibit its growth in vitro. Patients should be monitored for changes in tobramycin susceptibility.

Development of Resistance

In clinical studies, some increases from baseline to the end of the treatment period were observed in the tobramycin MIC for P. aeruginosa morphotypes. In general, a higher percentage of patients treated with TOBI Podhaler had increases in tobramycin MIC compared with placebo or patients treated with TOBI inhalation solution.

The clinical significance of changes in MICs for P. aeruginosa has not been clearly established in the treatment of cystic f