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. METHODS: A randomized, open-label, crossover study was performed. In 2 separate study visits, blood samples from 22 children were collected following TIS nebulization with I-neb (75 mg) and PARI-LC Plus (300 mg). Study visits were separated by 1 month, in which 1 of the study nebulizers was used twice daily. Tobramycin PK for both nebulizers was established using measured tobramycin concentrations and Bayesian PK modelling software. Hearing and renal function tests were performed to test for aminoglycoside associated toxicity. In addition to standard estimated glomerular filtration rate 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 estimated glomerular filtration rate revealed no abnormalities. However, increased urinary NAG/creatinine ratios at visit 2 for both nebulizers suggest 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 cystic fibrosis 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.

Small airway involvement in cystic fibrosis lung disease: routine spirometry as an early and sensitive marker.

BACKGROUND: In young children with cystic fibrosis (CF) the forced expiratory volume in 1 second (FEV1 ) is often normal and a more sensitive measure to detect early obstructive lung disease is needed. AIM: To evaluate the progression of selected spirometry parameters with age in a cohort of CF patients and healthy children aged 6 to 20 years. METHODS: Retrospective comparison of longitudinal spirometry data from CF patients with data from two cohort studies in healthy subjects. Quantile regression was used to calculate the longitudinal 10th percentile (P10 ), 50th percentile (P50 ), and 90th percentile (P90 ) of forced vital capacity (FVC), FEV1 , and the forced expiratory flow at 75% of FVC (FEF75 ). Sample size estimates were calculated using these three parameters as clinical trial endpoints. RESULTS: FVC, FEV1 , and FEF75 were all significantly lower in CF patients than healthy children. Abnormalities in FEF75 occurred at younger ages and remained substantially larger than abnormalities in FEV1 or FVC throughout childhood. Therefore, fewer patients would be required to detect a similar treatment effect if FEF75 is used as a primary endpoint compared with FEV1 or FVC. CONCLUSIONS: Our data support the use of FEF75 as a more sensitive marker of early CF lung disease than FEV1 and FVC, because abnormalities in FEF75 occur at younger age and FEF75 is diminished more than other parameters.