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

Abstract

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.

Cystic Fibrosis Foundation otolaryngology care multidisciplinary consensus recommendations

“…63 While the link between intravenous aminoglycosides and ototoxicity is clear, a connection between nebulized aminoglycosides and objective hearing loss is less certain. 64,65 While there are no data to demonstrate that ototoxic monitoring can prevent ototoxicity or improve quality of life in individuals with CF, this recommendation is made because identifying individuals with preexisting hearing loss or new ototoxicity symptoms would potentially allow for selection of less ototoxic therapies. The CFF does not recommend any specific audiologic or vestibular testing but further discussion can be found in the Supplemental File, p. 81.…”

“…Hearing loss caused by intravenous aminoglycosides occurs initially in higher frequencies (>8 kHz) and may extend into lower frequencies over time in some patients 63 . While the link between intravenous aminoglycosides and ototoxicity is clear, a connection between nebulized aminoglycosides and objective hearing loss is less certain 64,65 . While there are no data to demonstrate that ototoxic monitoring can prevent ototoxicity or improve quality of life in individuals with CF, this recommendation is made because identifying individuals with preexisting hearing loss or new ototoxicity symptoms would potentially allow for selection of less ototoxic therapies.…”

Biologically Relevant Murine Models of Chronic Pseudomonas aeruginosa Respiratory Infection

“…Utilising a clinically relevant treatment regimen of inhaled tobramycin, in our second model we aimed to develop a model of incomplete antibiotic clearance. Mice were infected i.n with 1 × 10 6 CFU of PAO1 and subsequently treated with tobramycin for 5 days by nebulisation [ 30 ].…”