Pharmacokinetics and Tolerability of Once Daily Double Dose Tobramycin Inhalation in Cystic Fibrosis Using Controlled and Conventional Nebulization.

Background: Better treatment outcomes in cystic fibrosis (CF) may be expected by changing standard twice daily (BID) tobramycin inhalation with the conventional nebulizer to once daily (OD) inhalation at double the standard BID dose with a controlled-inhalation nebulizer. We aimed to determine the pharmacokinetics and tolerability of inhaled double-dose tobramycin with the controlled-inhalation AKITA(®) and conventional PARI-LC(®) Plus nebulizer in patients with CF.

Methods: Randomized, open label, crossover study. Pharmacokinetics were assessed in 10 adult CF patients following inhalation of tobramycin (Bramitob(®)) at double the recommended BID dose with the AKITA (300 mg fill dose) and PARI-LC Plus (600 mg fill dose).

Results: No significant differences were found in pharmacokinetic parameters between the two nebulizers. Median maximum serum levels were 3.44 (2.25-5.49) and 2.84 (0.82-6.63) mg/L for AKITA and PARI-LC Plus, respectively. Trough serum levels were very low for both nebulizers: 0.03 (0.00-0.09) and 0.02 (0.00-0.06) mg/L for AKITA and PARI-LC Plus, respectively. Time to maximum level was comparable: 0.44 (0.08-0.96) and 0.40 (0.08-0.96) hours for AKITA and PARI-LC Plus, respectively. Serum levels were well below the toxic limit. Inhalations were well tolerated and no serious adverse events occurred. Nebulization time was 33% shorter with the AKITA.

Conclusions: OD tobramycin inhalation of the double standard BID dose with a controlled-inhalation and conventional nebulizer resulted in similar pharmacokinetics in the doses given, with serum levels below the toxic limit. Further research demonstrating clinical efficacy and safety of this treatment approach is required. Dutch trial register number NTR4525.