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.

Estimating peak oxygen uptake in adolescents with cystic fibrosis.

OBJECTIVES: To predict peak oxygen uptake (VO2 peak) from the peak work rate (W peak) obtained during a cycle ergometry test using the Godfrey protocol in adolescents with cystic fibrosis (CF), and assess the accuracy of the model for prognostication clustering. METHODS: Out of our database of anthropometric, spirometric and maximal exercise data from adolescents with CF (N=363; 140 girls and 223 boys; age 14.77 ± 1.73 years; mean expiratory volume in 1 s (FEV1%pred) 86.82 ± 17.77%), a regression equation was developed to predict VO2 peak (mL/min). Afterwards, this prediction model was validated with cardiopulmonary exercise data from another 60 adolescents with CF (28 girls, 32 boys; mean age 14.6 ± 1.67 years; mean FEV1%pred 85.43 ± 20.01%). RESULTS: We developed a regression model VO2 peak (mL/min)=216.3-138.7 × sex (0=male; 1=female)+11.5 × W peak; R(2)=0.91; SE of the estimate (SEE) 172.57. A statistically significant difference (107 mL/min; p<0.001) was found between predicted VO2 peak and measured VO2 peak in the validation group. However, this difference was not clinically relevant because the difference was within the SEE of the model. Furthermore, we found high positive predictive and negative predictive values for the model for prognostication clustering (PPV 50-87% vs NPV 82-94%). CONCLUSIONS: In the absence of direct VO2 peak assessment it is possible to estimate VO2 peak in adolescents with CF using only a cycle ergometer. Furthermore, the regression model showed to be able to discriminate patients in different prognosis clusters based on exercise capacity.