Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1     Pharmacodynamic properties

Pharmacotherapeutic group: Aminoglycoside Antibacterials, ATC code: J01GB01 
Mechanism of action
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, 97% of patients receiving TOBI achieved sputum concentrations 10 fold the highest P. aeruginosa MIC cultured from the patient, and 95% of patients receiving TOBI 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. However, the TOBI clinical studies showed that a microbiological report indicating in vitro drug resistance did not necessarily preclude a clinical benefit for the patient.

Most patients with P. aeruginosa isolates with tobramycin MICs <128 µg/ml at baseline showed improved lung function following treatment with TOBI. Patients with a P. aeruginosa isolate with a MIC  128 µg/ml at baseline are less likely to show a clinical response.
However, seven of 13 patients (54%) in the placebo-controlled trials who acquired isolates with MICs of  128 µg/ml while using TOBI had improvement in pulmonary function.
Over the entire 96 week duration of the extension studies, the tobramycin MIC50 for P.
aeruginosa increased from 1 to 2 μg/ml and the MIC90 increased from 8 to 32 μg/ml.

Based upon in vitro data and/or clinical trial experience, the organisms associated with pulmonary infections in CF may be expected to respond to TOBI therapy as follows: 
Susceptible                 Pseudomonas aeruginosa
Haemophilus influenzae
Staphylococcus aureus
Insusceptible               Burkholderia cepacia
Stenotrophomonas maltophilia
Alcaligenes xylosoxidans

Treatment with the TOBI 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
There is no evidence that patients treated with up to 18 months of TOBI were at a greater risk for acquiring B. cepacia, S. maltophilia or A. xylosoxidans, than would be expected in patients not treated with TOBI. Aspergillus species were more frequently recovered from the sputum of patients who received TOBI; however, clinical sequelae such as Allergic Bronchopulmonary Aspergillosis (ABPA) were reported rarely and with similar frequency as in the control group.

There are insufficient clinical safety and efficacy data in children < 6 years of age.

In an open-label uncontrolled study, 88 patients with CF (37 patients between 6 months and 6 years, 41 patients between 6 and 18 years of age and 10 patients above 18 years of age) with early (non-chronic) P. aeruginosa infection were treated for 28 days with TOBI. After 28 days, patients were randomised 1:1 to either stop (n=45) or to receive a further 28 days treatment (n=43).

Primary outcome was the median time to recurrence of P. aeruginosa (any strain) which was 26.1 and 25.8 months for the 28-day and 56-day groups, respectively. It was found that 93% and 92% of the patients were free of P. aeruginosa infection 1 month after the end of treatment in the 28-day and 56-day groups, respectively. The use of TOBI with a dosing regimen longer than 28 days continuous treatment, is not approved.

In a double-blind, randomized, placebo-controlled trial, 51 patients aged 3 months to less than 7 years with a confirmed diagnosis of CF and an early colonization with P. aeruginosa (defined as: either first positive culture overall or first positive culture after at least a 1-year history of negative cultures) were treated with TOBI 300 mg/5 mL or placebo, both inhaled via a nebuliser (PARI LC Plus™) twice daily for 28 days. Patients who were treated with anti- pseudomonal therapy in the previous year were excluded. A total of 26 patients were randomized to receive TOBI and 25 patients to placebo. The primary outcome was based on the proportion of patients free from P. aeruginosa colonization assessed by sputum/throat swab culture after completion of a 28-day treatment period which was 84.6% (22 out of 26 patients) for the TOBI group and 24% (6 out of 25 patients) for the placebo group (p<0.001).The frequency, type and severity of the observed adverse events in children < 7 years of age were consistent with the known safety profile of TOBI.
The use of TOBI is not indicated in children < 6 years of age (see section 4.2 Posology and method of administration).

Clinical efficacy

Two identically designed, double-blind, randomized, placebo-controlled, parallel group, 24- week clinical studies (Study 1 and Study 2) were conducted in cystic fibrosis patients with P.
aeruginosa. These studies enrolled 520 subjects who had a baseline FEV1 of between 25% and 75% of their predicted normal value. Patients who were less than six years of age, or who had a baseline creatinine of > 2 mg/dl, or who had Burkholderia cepacia isolated from sputum were excluded. In these clinical studies, 258 patients received TOBI therapy on an outpatient basis using a hand-held PARI LC PLUS™ Reusable Nebuliser with a DeVilbiss™ Pulmo- Aide™ compressor.

In each study, TOBI-treated patients experienced significant improvement in pulmonary function and significant reduction in the number of P. aeruginosa colony forming units (CFUs) in sputum during the on-drug periods. The mean FEV1 remained above baseline in the 28-day off-drug periods, although it reversed somewhat on most occasions. Sputum bacterial density returned to baseline during the off-drug periods. Reductions in sputum bacterial density were smaller in each successive cycle.

Patients treated with TOBI experienced fewer hospitalization days and required fewer days of parenteral anti-pseudomonal antibiotics on average, compared with placebo patients.

In open label extensions to the studies 1 and 2, there were 396 patients of the 464 who completed either of the two 24 week double blind studies. In total, 313, 264 and 120 patients completed treatment with TOBI for 48, 72 and 96 weeks respectively.
The rate of lung function decline was significantly lower following initiation of TOBI therapy than that observed among patients receiving placebo during the double blind randomized treatment period. The estimated slope in the regression model of lung function decline was -6.52% during the blinded placebo treatment and -2.53% during TOBI treatment (p=0.0001).

Pharmacokinetic Properties

5.2     Pharmacokinetic properties

Absorption
Tobramycin is a cationic polar molecule that does not readily cross epithelial membranes. The systemic exposure to tobramycin after inhalation of TOBI is expected to result from pulmonary absorption of the dose fraction delivered to the lungs as tobramycin is not absorbed to any appreciable extent when administered via the oral route. The bioavailability of TOBI may vary because of individual differences in nebuliser performance and airway pathology.

Sputum concentrations:
Ten minutes after inhalation of the first 300 mg dose of TOBI, the average sputum concentration of tobramycin was 1,237 g/g (range: 35 to 7,414 g/g). Tobramycin does not accumulate in sputum; after 20 weeks of therapy with the TOBI regimen, the average sputum concentration of tobramycin 10 minutes after inhalation was 1,154 g/g (range: 39 to 8,085 g/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 mean serum concentration of tobramycin 1 hour after inhalation of a single 300 mg dose of TOBI by CF patients was 0.95 µg/ml (range: below limit of quantitation [BLQ] – 3.62µg/ml). After 20 weeks of therapy on the TOBI regimen, the mean serum tobramycin concentration 1 hour after dosing was 1.05 µg/ml (range: BLQ – 3.41µg/ml). For comparison the peak concentrations after intravenous or intramuscular administration of a single tobramycin dose of 1.5 to 2mg/kg typically range from 4 to 12 µg/ml.

Distribution
Following administration of TOBI, tobramycin remains concentrated primarily in the airways.
Less than 10% of tobramycin is bound to plasma proteins.

Biotransformation
Tobramycin is not metabolized and is primarily excreted unchanged in the urine.
Elimination
The elimination of tobramycin administered by the inhalation route has not been studied.
Following intravenous administration, tobramycin is eliminated principally by glomerular filtration of the unchanged compound. The apparent terminal half-life of tobramycin in serum after inhalation of a 300 mg single dose of TOBI was 3 hours in cystic fibrosis patients.
Renal function is expected to affect the exposure to tobramycin, however data are not available as patients with serum creatinine 2 mg/dl (176,8 mol/l) or more or blood urea nitrogen (BUN) 40 mg/dl or more were not included in clinical studies.

Unabsorbed tobramycin following TOBI administration is probably eliminated primarily in expectorated sputum.