Tobi Pharmacology, Pharmacokinetics, Studies, Metabolism - Tobramycin

Tobi Pharmacology, Pharmacokinetics, Studies, Metabolism - Tobramycin

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.

CLINICAL STUDIES

Two identically designed, double-blind, randomized, placebo-controlled, parallel group, 24-week clinical studies (Study 1 and Study 2) at a total of 69 cystic fibrosis centers in the United States were conducted in cystic fibrosis patients with P. aeruginosa . Subjects who were less than six years of age, had a baseline creatinine of > 2 mg/dL, or had Burkholderia cepacia isolated from sputum were excluded. All subjects had baseline FEV ₁ % predicted between 25% and 75%. In these clinical studies, 258 patients received TOBI therapy on an outpatient basis (see Table 2) using a hand-held PARI LC PLUS reusable nebulizer with a DeVilbiss Pulmo-Aide compressor.

All patients received either TOBI or placebo (saline with 1.25 mg quinine for flavoring) in addition to standard treatment recommended for cystic fibrosis patients, which included oral and parenteral anti-pseudomonal therapy, (beta) ₂ -agonists, cromolyn, inhaled steroids, and airway clearance techniques. In addition, approximately 77% of patients were concurrently treated with dornase alfa (PULMOZYME®, Genentech).

In each study, TOBI-treated patients experienced significant improvement in pulmonary function. Improvement was demonstrated in the TOBI group in Study 1 by an average increase in FEV ₁ % predicted of about 11% relative to baseline (Week 0) during 24 weeks compared to no average change in placebo patients. In Study 2, TOBI treated patients had an average increase of about 7% compared to an average decrease of about 1% in placebo patients.

In each study, TOBI therapy resulted in a significant reduction in the number of P. aeruginosa colony forming units (CFUs) in sputum during the on-drug periods. 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 were hospitalized for an average of 5.1 days compared to 8.1 days for placebo patients. Patients treated with TOBI required an average of 9.6 days of parenteral anti-pseudomonal antibiotic treatment compared to 14.1 days for placebo patients. During the six months of treatment, 40% of TOBI patients and 53% of placebo patients were treated with parenteral anti-pseudomonal antibiotics.

The relationship between in vitro susceptibility test results and clinical outcome with TOBI therapy is not clear. However, four TOBI patients who began the clinical trial with P. aeruginosa isolates having MIC values ≥128 µg/mL did not experience an improvement in FEV ₁ or a decrease in sputum bacterial density.

Treatment with TOBI did not affect the susceptibility of the majority of P. aeruginosa isolates during the six month studies. However, some P. aeruginosa isolates did exhibit increased tobramycin MICs. The percentage of patients with P. aeruginosa isolates with tobramycin MICs ≥ 16 µg/mL was 13% at the beginning, and 23% at the end of six months of the TOBI regimen.