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The pharmacokinetics and toxicity of morning vs. evening tobramycin dosing for pulmonary exacerbations of cystic fibrosis: A randomised comparison

Smyth, A.R.; Knox, A.J.; Prayle, A.P.; Jain, K.; Touw, D.J.; Koch, B.C.P.; Knox, Alan J.; Watson, A.; Smyth, Alan R.

Authors

A.R. Smyth

A.J. Knox

A.P. Prayle

K. Jain

D.J. Touw

B.C.P. Koch

Alan J. Knox

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ALAN SMYTH alan.smyth@nottingham.ac.uk
Professor of Child Health



Abstract

Background: Circadian variation in renal toxicity of aminoglycosides has been demonstrated in animal and human studies. People with CF are frequently prescribed aminoglycosides. Altered pharmacokinetics of aminoglycosides are predictive of toxicity.
Aim: To investigate whether the time of day of aminoglycoside administration modulates renal excretion of tobramycin and toxicity in children with CF. To determine whether circadian rhythms are disrupted in children with CF during hospital admission.
Methods: Children (age 5–18 years) with CF scheduled for tobramycin therapy were randomly allocated to receive tobramycin at 0800 or 2000 h. Serum tobramycin levels were drawn at 1 h and between 3.5 and 5 h post-infusion between days 5 and 9 of therapy. Melatonin levels were measured serially at intervals from 1800 h in the evening until 1200 h on the next day. Circadian rhythm was categorised as normal when dim light melatonin onset was demonstrated between 1800 and 2200 h and/or peak melatonin levels were observed during the night. Weight and spirometry were measured at the start and end of the therapy. Urinary biomarkers of kidney toxicity (KIM1, NAG, NGAL, IL-18 and CysC) were assayed at the start and end of the course of tobramycin.
Results: Eighteen children were recruited to the study. There were no differences in renal clearance between the morning and evening groups. The increase in urinary KIM-1 was greater in the evening dosage group compared to the morning group (mean difference, 0.73 ng/mg; 95% CI, 0.14 to 1.32; p = 0.018). There were no differences in the other urinary biomarkers. There was normal circadian rhythm in 7/11 participants (64%).
Conclusions: Renal elimination of tobramycin was not affected by the time of day of administration. Urinary KIM-1 raises the possibility of greater nephrotoxicity with evening administration. Four children showed disturbed circadian rhythm and high melatonin levels (ClinicalTrials.gov NCT01207245).

Journal Article Type Article
Publication Date 2016-07
Journal Journal of Cystic Fibrosis
Print ISSN 1569-1993
Electronic ISSN 1873-5010
Publisher Elsevier
Peer Reviewed Peer Reviewed
Volume 15
Issue 4
Pages 510-517
APA6 Citation Smyth, A., Knox, A., Prayle, A., Jain, K., Touw, D., Koch, B., …Smyth, A. R. (2016). The pharmacokinetics and toxicity of morning vs. evening tobramycin dosing for pulmonary exacerbations of cystic fibrosis: A randomised comparison. Journal of Cystic Fibrosis, 15(4), 510-517. https://doi.org/10.1016/j.jcf.2015.07.012
DOI https://doi.org/10.1016/j.jcf.2015.07.012
Keywords Cystic fibrosis; Aminoglycosides; Toxicity; Circadian rhythm
Publisher URL http://www.sciencedirect.com/science/article/pii/S1569199315001745
Copyright Statement Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by-nc-nd/4.0
Additional Information This article is maintained by: Elsevier; Article Title: The pharmacokinetics and toxicity of morning vs. evening tobramycin dosing for pulmonary exacerbations of cystic fibrosis: A randomised comparison; Journal Title: Journal of Cystic Fibrosis; CrossRef DOI link to publisher maintained version: https://doi.org/10.1016/j.jcf.2015.07.012; Content Type: article; Copyright: © 2015 The Authors. Published by Elsevier B.V. on behalf of European Cystic Fibrosis Society.

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