Serum tobramycin levels following delivery of tobramycin (Tobi®) via eFlow® advanced nebuliser in children with cystic fibrosis

Guy, E.; Bosomworth, M.; Denton, M.; Conway, S.P.; Brownlee, K.; Lee, T.W.R.

doi:10.1016/j.jcf.2010.03.007

Cited by 11 publications

(6 citation statements)

References 25 publications

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“…No data exist for KIM‐1 and only few data are available in literature regarding NAG (reference) values in children with CF using TIS. One study measured NAG in urinary samples of 10 CF patients aged 2–16 years who received twice daily 300 mg TIS treatment with the eFlow nebulizer and 2 other studies reported NAG/creatinine ratios of, respectively, 4 and 14 patients in the age range of 3–22 years receiving 40–80 mg TIS twice daily with a jet nebulizer . Median NAG/creatinine ratios measured in our study were in the same order of magnitude as in the studies mentioned above.…”

Section: Discussionsupporting

confidence: 78%

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

Velzen

Uges

Heijerman

et al. 2019

Brit J Clinical Pharma

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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.

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Section: Discussionsupporting

confidence: 78%

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

Velzen

Uges

Heijerman

et al. 2019

Brit J Clinical Pharma

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“…Tobramycin- and aminoglycoside-induced ototoxicity reports range from nearly absent to approximately 35% of cystic fibrosis patients (Mulheran et al 2001, 2006; Piltcher et al 2003; Cheng et al 2009; Guy et al 2010; Martins et al 2010; Scheenstra et al 2010; Al-Malky et al 2011; Hennig et al 2014) with an increased risk of aminoglycoside-induced hearing loss with repeated and higher cumulative doses. The majority of adolescent and adult cystic fibrosis patients are colonized with Pseudomonas aeruginosa ( P. aeruginosa) (Cystic Fibrosis Foundation Registry 2011).…”

Section: Discussionmentioning

confidence: 99%

d -Methionine reduces tobramycin-induced ototoxicity without antimicrobial interference in animal models

Fox

Cooper

Speil

et al. 2016

Journal of Cystic Fibrosis

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Background Tobramycin is a critical cystic fibrosis treatment however it causes ototoxicity. This study tested D-methionine protection from tobramycin-induced ototoxicity and potential antimicrobial interference. Methods Auditory brainstem responses (ABR) and outer hair cell (OHC) quantifications measured protection in guinea pigs treated with tobramycin and a range of D-methionine doses. In vitro antimicrobial interference studies tested inhibition and post antibiotic effect assays. In vivo antimicrobial interference studies tested normal and neutropenic E. coli murine survival and intraperitoneal lavage bacterial counts. Results D-methionine conferred significant ABR threshold shift reductions. OHC protection was less robust but significant at 20 kHz in the 420 mg/kg/day group. In vitro studies did not detect D-methionine-induced antimicrobial interference. In vivo studies did not detect D-methionine-induced interference in normal or neutropenic mice. Conclusions D-methionine protects from tobramycin-induced ototoxicity without antimicrobial interference. The study results suggest D-met as a potential otoprotectant from clinical tobramycin use in cystic fibrosis patients.

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“…NAG is a proximal tubule lysosomal enzyme that has been extensively characterized as a sensitive, persistent, and robust urinary indicator of renal tubular injury . Urinary NAG levels have been used to evaluate the nephrotoxicity associated with different AG dosing regimens, and CF patients receiving inhaled AGs have been found to have increased urinary NAG levels . Although more limited, additional studies have shown increased urinary NAG levels in patients who were also receiving NSAID therapy …”

Section: Discussionmentioning

confidence: 99%

High-dose ibuprofen is not associated with increased biomarkers of kidney injury in patients with cystic fibrosis

et al. 2013

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High-dose ibuprofen (IBU) may slow the decline of lung function in patients with cystic fibrosis (CF), but its use has been limited due to concerns over renal and gastrointestinal toxicity. In this pilot study, we examined the association of IBU with markers of acute kidney injury (AKI) in patients with CF. The effect of aminoglycoside (AG) exposure on AKI biomarkers was also examined. The AKI markers, kidney injury molecule-1 (KIM), N-acetyl-β-glucosaminidase (NAG) and urine protein, normalized for creatinine, were chosen as they are more sensitive indicators of kidney injury than changes in serum creatinine. Urine samples from 52 patients, 26 from patients who were treated with IBU, were analyzed. There was no significant association between IBU treatment and KIM-1, NAG or protein levels, compared to patients never treated with IBU. While there was an association between AG courses and KIM-1 levels, there were no differences in biomarker levels between IBU and non-IBU groups with respect to AG courses. These preliminary results suggest that IBU treatment in patients with CF may be safe with respect to renal toxicity.

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Serum tobramycin levels following delivery of tobramycin (Tobi®) via eFlow® advanced nebuliser in children with cystic fibrosis

Abstract: Serum tobramycin levels over 1mg/L can occur 1h post 300mg TOBI delivered by eFlow. Raised urinary NAG levels suggest that some children may have some associated early renal toxicity.

Cited by 11 publications

References 25 publications

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

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

d -Methionine reduces tobramycin-induced ototoxicity without antimicrobial interference in animal models

High-dose ibuprofen is not associated with increased biomarkers of kidney injury in patients with cystic fibrosis

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