Pharmacokinetic Study of Bramitob® Administered for Inhalation by PARI eFlow® vs PARI LC® PLUS Nebulizer

• Plasma tobramycin pharmacokinetic parameters (Cmax, tmax and AUC0-t) after inhalation of Bramitob® using PARI eFlow® nebulizer vs PARI LC® PLUS nebulizer [ Time Frame: on day 1 ] [ Designated as safety issue: No ]
• Sputum tobramycin pharmacokinetic parameters (Cmax, tmax and AUC0-t) after inhalation of Bramitob® using PARI eFlow® nebulizer vs PARI LC® PLUS nebulizer [ Time Frame: on day 1 and on day 28 ] [ Designated as safety issue: No ]
• Accumulation of tobramycin in plasma and sputum after repeated doses calculated as the ratio: AUC0-t DAY 28 / AUC0-t DAY 1 and Cmax DAY 28 / Cmax DAY 1 [ Time Frame: day 1 - day 28 ] [ Designated as safety issue: No ]
• Safety assessed by adverse events, adverse drug reactions, incidence of bronchospasm, laboratory parameters, physical examination, body weight, vital signs results [ Time Frame: day1-day28 ] [ Designated as safety issue: Yes ]
• Number of patients with minimum plasma tobramycin levels Cmin > 2mcg/mL and maximum plasma tobramycin levels Cmax > 12 mcg/mL [ Time Frame: on day 28 ] [ Designated as safety issue: Yes ]
• Time necessary for the nebulization of the dose [ Time Frame: on day 1 and on day 28 ] [ Designated as safety issue: No ]

The purpose of this study is to assess pharmacokinetic and safety comparability of Bramitob® when administered for inhalation by using PARI eFlow® rapid electronic nebulizer vs PARI LC® PLUS nebulizer in Cystic Fibrosis Patients infected with Pseudomonas Aeruginosa

• Drug: Bramitob® administered by PARI LC® PLUS nebulizer
  (tobramycin 300mg /4mL) solution administered by inhalation twice daily for 28 days
  Other Name: Bramitob®, Tobrineb®, Actitob®
• Drug: Bramitob® administered by PARI eFlow® rapid electronic nebulizer
  (tobramycin 300mg /4mL) solution administered by inhalation twice daily for 28 days
  Other Name: Bramitob®, Tobrineb®,Actitob®

• Active Comparator: PARI LC® PLUS nebulizer
  Intervention: Drug: Bramitob® administered by PARI LC® PLUS nebulizer
• Active Comparator: PARI eFlow® rapid electronic nebulizer
  Intervention: Drug: Bramitob® administered by PARI eFlow® rapid electronic nebulizer

Main inclusion Criteria:

• Patients of either sex aged ≥ 18 years;
• Clinical diagnosis of cystic fibrosis (patients registered in the National Registry of cystic fibrosis or other documents, if applicable, depending on country legislation);
• Positive response (sweat chloride concentration ≥ 60 mmol/l) in the standard sweat test documented in the clinical records or sweat chloride concentration ≥ 40 mmol/l and at least two gene mutations consistent with CF documented in the clinical records;
• Chronic colonization of Pseudomonas aeruginosa
• FEV1 ≥ 35% of the predicted normal value calculated according to the recommendation of the Official Statement of the European Respiratory Society and American Thoracic Society

Main exclusion Criteria:

• Evidence of impaired renal function (serum creatinine level ≥ 1.5 mg/dl);
• Evidence of impaired auditory function (auditory threshold in either ear above 20 dB at frequencies between 250 and 8000Hz);
• Sputum culture containing Burkholderia cepacia;
• Received loop diuretics within 7 days before study drug administration;