Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Aminoglycoside antibacterials, ATC code: J01GB01.
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.
Breakpoints
Established susceptibility breakpoints for parenteral administration of tobramycin are inappropriate in the aerosolised administration of the medicinal product. Cystic fibrosis (CF) sputum exhibits an inhibitory action on the local biological activity of nebulised aminoglycosides. This necessitates sputum concentrations of aerosolised tobramycin to be some ten and twenty–five fold above the Minimum Inhibitory Concentration (MIC) for, respectively, P. aeruginosa growth suppression and bactericidal activity. In controlled clinical trials, 90% of patients receiving tobramycin achieved sputum concentrations 10 fold the highest P. aeruginosa MIC cultured from the patient, and 84% of patients receiving tobramycin achieved 25 fold the highest MIC. Clinical benefit is still achieved in a majority of patients who culture strains with MIC values above the parenteral breakpoint.
Susceptibility
In the absence of conventional susceptibility breakpoints for the nebulised route of administration, caution must be exercised in defining organisms as susceptible or insusceptible to nebulised tobramycin.
In clinical studies with inhaled tobramycin, most patients (88%) with P. aeruginosa isolates with tobramycin MICs <128 µg/mL at baseline showed improved lung function following treatment with tobramycin. Patients with a P. aeruginosa isolate with a MIC 128 µg/mL at baseline are less likely to show a clinical response.
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 therapy as follows: 

Susceptible                 Pseudomonas aeruginosa

Haemophilus influenzae

Staphylococcus aureus
Insusceptible               Burkholderia cepacia

Stenotrophomonas maltophilia

Alcaligenes xylosoxidans

Treatment with tobramycin regimen in clinical studies showed a small but clear increase in tobramycin, amikacin and gentamicin Minimum Inhibitory Concentrations for P. aeruginosa isolates tested. Each additional 6 months of treatment resulted in incremental increases similar in magnitude to that observed in the 6 months of controlled studies. The most prevalent aminoglycoside resistance mechanism seen in P. aeruginosa isolated from chronically infected CF patients is impermeability, defined by a general lack of susceptibility to all aminoglycosides.
P. aeruginosa isolated from CF patients has also been shown to exhibit adaptive aminoglycoside resistance that is characterised by a reversion to susceptibility when the antibiotic is removed.
Other Information
In controlled clinical studies, treatment with Bramitob carried out according to alternate cycles as described above, led to an improvement in lung function, with results maintained above baseline throughout therapy and 28 day periods off therapy.
In clinical trials with tobramycin there are no data in patients aged less than 6 years.
There is no evidence that patients treated with up to 18 months with tobramycin were at a greater risk for acquiring B. cepacia, S. maltophilia or A. xylosoxidans, than would be expected in patients not treated with tobramycin. Aspergillus species were more frequently recovered from the sputum of patients who received tobramycin; however, clinical sequelae such as Allergic Bronchopulmonary Aspergillosis (ABPA) were reported rarely and with similar frequency as in the control group.

Pharmacokinetic Properties

5.2 Pharmacokinetic properties
Absorption and distribution
Following oral administration only 0.3-0.5% of the drug appears in urine to prove systemic absorption. After administration via nebuliser in 6 cystic fibrosis patients, mean absolute bioavailability was about 9.1% of the dose. Systemic absorption of tobramycin is very low when administered by aerosol inhalation, with a limited uptake of the inhaled drug into the systemic circulation, it is estimated that approximately 10% of the mass of drug initially nebulised is deposited in the lungs and the remaining 90% either remains in the nebuliser, is impacted on the oro-pharynx and swallowed, or is exhaled into the atmosphere.
Sputum concentrations: Ten minutes after inhalation of the first 300 mg dose of Bramitob, the average sputum concentration of tobramycin was 695.6 μg/g (range: 36 to 2,638 μg/g).
Tobramycin does not accumulate in sputum; after 20 weeks of therapy with the Bramitob regimen, the average sputum concentration of tobramycin 10 minutes after inhalation was 716.9 μg/g (range: 40 to 2,530 μg/g). High variability of sputum tobramycin concentrations was observed. Two hours after inhalation, sputum concentrations declined to approximately 14% of tobramycin levels measured at 10 minutes after inhalation.
Serum concentrations: The median serum concentration of tobramycin 1 hour after inhalation of a single 300 mg dose of Bramitob by CF patients was 0.68 μg/mL (range: 0.06μg/mL – 1.89μg/mL). After 20 weeks of therapy on the tobramycin regimen, the median serum tobramycin concentration 1 hour after dosing was 1.05 μg/mL (range: BLQ- 3.41μg/mL).
Elimination
The elimination of tobramycin administered by the inhalation route has not been studied.
Following intravenous administration, systemically absorbed tobramycin is eliminated principally by glomerular filtration. The elimination half-life of tobramycin from serum is approximately 2 hours. Less than 10% of tobramycin is bound to plasma proteins.
Unabsorbed tobramycin following tobramycin administration is probably eliminated primarily in expectorated sputum.