Tobramycin Inhalation (Page 4 of 7)

Sputum Concentrations

Thirty minutes after inhalation of the first 300 mg dose of Tobramycin Inhalation Solution, the maximum geometric mean concentration of tobramycin was 814 mcg/g (ranging from 23 to 2843 mcg/g) in sputum. High variability of tobramycin concentration in sputum was observed. Three hours after inhalation started, sputum tobramycin concentrations declined to approximately 15% of those observed at 30 minutes. After four weeks of therapy with Tobramycin Inhalation Solution average mean sputum tobramycin concentrations obtained 10 minutes following administration were 717 mcg/g.

Distribution

Following administration of Tobramycin Inhalation Solution, tobramycin remains concentrated primarily in the airways. Binding of tobramycin to serum proteins is negligible.

Elimination

Tobramycin is not metabolized. The elimination half-life of tobramycin from serum is approximately two hours after intravenous (IV) administration. The elimination half-life following the inhalation of Tobramycin Inhalation Solution is approximately 4.4 hours. Assuming tobramycin absorbed following inhalation behaves similarly to tobramycin following intravenous administration, systemically absorbed tobramycin is eliminated principally by glomerular filtration. Unabsorbed tobramycin following inhalation is likely eliminated in expectorated sputum.

12.4 Microbiology

Mechanism of Action

Tobramycin, an aminoglycoside antibacterial, acts primarily by disrupting protein synthesis in the bacterial cell which eventually leads to death of the cell. Tobramycin has activity against a wide range of gram-negative bacteria including P. aeruginosa. It is bactericidal at or above the minimal inhibitory concentration (MIC) needed to inhibit growth of bacteria.

Mechanism of Resistance

The predominant mechanism of resistance to tobramycin in P. aeruginosa isolated from CF patients is impermeability and to a lesser extent enzymatic modification and other mechanisms which cumulatively lead to decreased susceptibility of P. aeruginosa to tobramycin.

Cross Resistance

Cross resistance between aminoglycosides exists but the cross resistance is variable.

Development of Resistance

Treatment for six months with Tobramycin Inhalation Solution in one clinical trial did not affect the susceptibility of the majority of P. aeruginosa isolates tested; however, increases in minimal inhibitory concentrations (MIC) were noted in some patients. The clinical significance of this information has not been clearly established in the treatment of cystic fibrosis patients.

Susceptibility Testing

The clinical microbiology laboratory should provide cumulative results of the in vitro susceptibility test results for antimicrobial drugs used in local hospitals and practice areas to the physicians as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting the most effective antimicrobial.

Susceptibility Testing Techniques

Dilution Techniques

Quantitative methods can be used to determine the minimum inhibitory concentration (MIC) of tobramycin that will inhibit the growth of the bacteria being tested. The MIC provides an estimate of the susceptibility of bacteria to tobramycin. The MIC should be determined using a standardized procedure.3 , 5 Standardized procedures are based on a dilution method (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of tobramycin powder.

Diffusion Techniques

Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure requires the use of standardized inoculum concentrations.4 , 5 This procedure uses paper disks impregnated with 10 mcg of tobramycin to test the susceptibility of bacteria to tobramycin.

Susceptibility Test Interpretive Criteria

In vitro susceptibility test interpretive criteria for inhaled tobramycin have not been determined. The relation of the in vitro MIC and/or disk diffusion susceptibility test results to clinical efficacy of inhaled tobramycin against the bacteria tested should be monitored.

Quality Control Parameters for Susceptibility Testing

In vitro susceptibility test quality control parameters exist for tobramycin so that laboratories that test the susceptibility of bacterial isolates to tobramycin can determine if the susceptibility test is performing correctly. Standardized dilution techniques and diffusion methods require the use of laboratory control bacteria to monitor the technical aspects of the laboratory procedures. Standard tobramycin powder should provide the following MIC and a 10 mcg tobramycin disk should produce the following zone diameters with the indicated quality control strains (Table 2).

Table 2: Acceptable Quality Control Ranges for Tobramycin

Bacteria

MIC Range

(mcg/mL)

Disk Diffusion Zone

Diameter (mm)

Pseudomonas æruginosa

ATCC 27853

0.25-1

19-25

Other

No trends in the treatment-emergent isolation of other bacterial respiratory pathogens such as Burkholderia cepacia, Stenotrophomonas maltophilia, Achromobacter xylosoxidans, or Staphylococcus aureus were observed in clinical trials of Tobramycin Inhalation Solution relative to placebo. There was a slight increase in isolation of Candida spp in sputum at the end of the Tobramycin Inhalation Solution treatment cycle in clinical trials.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

A two-year rat inhalation toxicology study to assess carcinogenic potential of an inhaled solution of tobramycin has been completed. Rats were exposed to tobramycin for up to 1.5 hours per day for 95 weeks. Serum levels of tobramycin up to 35 mcg/mL were measured in rats, 35x the average 1 mcg/mL exposure levels observed in cystic fibrosis patients in clinical trials. There was no drug-related increase in the incidence of any variety of tumors.

Additionally, tobramycin has been evaluated for genotoxicity in a battery of in vitro and in vivo tests. The Ames bacterial reversion test, conducted with five tester strains, failed to show a significant increase in revertants with or without metabolic activation in all strains. Tobramycin was negative in the mouse lymphoma forward mutation assay, did not induce chromosomal aberrations in Chinese hamster ovary cells, and was negative in the mouse micronucleus test.

Subcutaneous administration of up to 100 mg/kg of tobramycin did not affect mating behavior or cause impairment of fertility in male or female rats.

14 CLINICAL STUDIES

Two, double-blind, randomized, placebo-controlled, parallel group clinical studies (Study 1 and Study 2), which randomized and dosed 306 patients, were conducted in cystic fibrosis patients with P. aeruginosa. The osmolality of the drug formulation used in these studies differed from the to-be-marketed product. To rely upon the efficacy and safety established in the placebo-controlled studies, an additional study was conducted as a bridge to the to-be-marketed drug. The bridging study assessed the efficacy and tolerability of aerosolized Tobramycin Inhalation Solution with osmolality similar to Tobramycin Inhalation Solution over a 4-week treatment in 324 patients with cystic fibrosis. Results of this study showed that the Tobramycin Inhalation Solution in this study had similar efficacy as that seen in the placebo-controlled studies.

The compressors in the placebo-controlled studies and the bridging study differed from the PARI VIOS compressor to be used with Tobramycin Inhalation Solution. In vitro cascade impaction studies demonstrated that the various compressors used in the clinical trials delivered equivalent doses and respirable fractions of the to-be-marketed Tobramycin Inhalation Solution and TOBI with the marketed compressor (PARI VIOS) when used with the same nebulizer (PARI LC Plus Reusable nebulizer).

All subjects enrolled in both efficacy studies had baseline FEV1 % predicted ≥ 40% and ≤ 80% (mean baseline FEV1 of 60% of predicted normal) and infected with P. aeruginosa. Subjects who were less than 6 years of age, or who had a baseline creatinine of ≥ 1.5 mg/dL, or who had Burkholderia cepacia isolated from sputum were excluded. A total of 190 patients, 29 in Study 1 and 161 in Study 2, received Tobramycin Inhalation Solution therapy on an outpatient basis. Of these, 55% were males and 45% were females. Eighty-two (43.2%) patients were between 6 and 12 years of age, 54 (28.4%) patients were between 13 and 17 years of age, and the remaining 54 (28.4%) patients were greater than 17 years of age. Of the patients who received Tobramycin Inhalation Solution, only 89.7% of patients in Study 1 had at least one concomitant medication, while all patients in Study 2 also received at least one concomitant medication. These concomitant medications include mucolytics, steroidal and nonsteroidal anti-inflammatory drugs, bronchodilators, rehabilitative physiotherapies and if necessary, antibiotics for bacterial infections other than P. aeruginosa.

Study 1

Study 1 was a double-blind, single cycle study that randomized 59 patients to receive Tobramycin Inhalation Solution (n=29) or placebo (n=30) for one cycle of treatment (28 days on treatment followed by 28 days off treatment). All patients were ≤ 30 years of age (mean age 12.6 years) and 46% were females. All randomized patients were included in the primary analysis except for one patient who had missing baseline information.

Tobramycin Inhalation Solution significantly improved lung function compared with placebo as measured by the absolute change in FEV1 % predicted from baseline to the end of Cycle 1 dosing in the primary analysis population. Treatment with Tobramycin Inhalation Solution and placebo resulted in absolute increases in FEV1 % predicted of 16% and 5%, respectively (LS mean difference = 11%; 95% CI: 3, 19; p=0.003). This analysis is adjusted for the covariate of baseline FEV1 % predicted, using multiple imputation for missing data. Figure 1 shows the average change in FEV1 % predicted over eight weeks.

Study 2

Study 2 was a randomized, double-blind, 3-cycle, placebo-controlled trial. A total of 247 eligible patients were randomized 2:1 to receive three cycles of Tobramycin Inhalation Solution (n=161) or placebo (n=86). As in Study 1, each cycle comprised 28 days on treatment followed by 28 days off treatment. All patients were ≤46 years of age (mean age 14.8 years) and 44.9% were females. In this study, two randomized patients in the placebo group were not included in the primary efficacy analysis; one withdrew consent without taking any trial medication and the other withdrew due to an adverse drug reaction.

Tobramycin Inhalation Solution significantly improved lung function compared with placebo as measured by the absolute change in FEV1 % predicted from baseline to the end of Cycle 3 “ON” period. Treatment with Tobramycin Inhalation Solution and placebo resulted in absolute increases in FEV1 % predicted of 7% and 1%, respectively (LS mean difference = 6%; 95% CI: 3, 10; p<0.001). This analysis is adjusted for the covariate of baseline FEV1 % predicted, using multiple imputation for missing data. Figure 1 shows the average change in FEV1 % predicted over 24 weeks from Study 2.

Figure 1: FEV1 % of Predicted Normal – Absolute Change from Baseline (Adjusted mean) — ITT Population

FEV1
(click image for full-size original)

In Study 2, 9.9% of patients treated with Tobramycin Inhalation Solution and 24.7% of patients who received placebo had unplanned hospitalizations due to the disease.

Also in Study 2, 6.2% of patients treated with Tobramycin Inhalation Solution and 16.5% of placebo patients received parenteral tobramycin.

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