Pharmacokinetics and safety of tobramycin nebulization with the I-neb® and PARI-LC Plus® in children with cystic fibrosis: a randomized, crossover study

AIMS: We aimed to compare the pharmacokinetics (PK) and safety profile of tobramycin inhalation solution (TIS) using the I-neb device to the standard PARI-LC® Plus nebulizer in children with cystic fibrosis (CF).

METHODS: A randomized, open-label, crossover study was performed. In two separate study visits blood samples from 22 children were collected following TIS nebulization with the I-neb (75 mg) and PARI-LC Plus (300 mg). Study visits were separated by one month, in which one of the study nebulizers was used twice daily. Tobramycin PK for both nebulizers was established using measured tobramycin concentrations and Bayesian pharmacokinetic modelling software. Hearing and renal function tests were performed to test for aminoglycoside associated toxicity. In addition to standard eGFR values, biomarkers for tubular injury (KIM-1 and NAG) were measured. Patient and nebulizer satisfaction were assessed.

RESULTS: Inhalations were well tolerated and serum trough concentrations below the predefined toxic limit were reached with no significant differences in PK parameters between nebulizers. Results of audiometry and eGFR revealed no abnormalities. Increased urinary NAG/creatinine ratios at visit 2 for both nebulizers suggest, however, TIS-induced subclinical tubular kidney injury. Nebulization time was 50% shorter and patient satisfaction was significantly higher with the I-neb.

CONCLUSIONS: Nebulization of 75 mg TIS with the I-neb in children with CF resulted in comparable systemic exposure to 300 mg TIS with the PARI-LC Plus and was well tolerated and preferred over the PARI-LC Plus. Long-term safety of TIS nebulization should be monitored clinically, especially regarding the effects on tubular kidney injury.