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Population Pharmacokinetics of Tobramycin in Patients With and Without Cystic Fibrosis

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Abstract

Background and Objectives

While several studies have examined the pharmacokinetics of tobramycin in patients with cystic fibrosis (CF), there is no consensus on whether they differ in patients with and without CF. The objectives of this study were to identify covariates which explain pharmacokinetic variability and to examine whether having the disease CF in itself alters these relationships and drug dose requirements.

Methods

To investigate this issue, a population pharmacokinetic meta-analysis of data from eight centres was undertaken. NONMEM® 7.2 was used to analyse the data, which comprised 4,514 concentration–time measurements from 465 adults and children with CF and 1,095 concentration–time measurements from 267 adults and children without CF.

Results

Tobramycin disposition was well described by a two-compartment model with first-order elimination. Patient age, fat-free mass, serum creatinine concentration and sex were identified as significant covariates in the final model. Fat-free mass was superior to total bodyweight as a descriptor of clearance, volume of distribution of the central and peripheral compartments and inter-compartmental clearance. CF as an independent disease-specific factor had no significant influence on the pharmacokinetics of tobramycin at any stage during covariate model building. An optimal dose of 11 mg/kg every 24 h was defined for CF patients using a utility function approach.

Conclusion

The pharmacokinetics of tobramycin do not differ significantly in CF patients compared with patients without CF when subject age, fat-free mass, sex and renal function are taken into consideration. Variations in tobramycin dosing between CF and non-CF patients should therefore reflect target concentrations or exposures based on differences in expected pathogen sensitivity and not the presence of CF.

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Acknowledgments

We would like to acknowledge Professor Sander Vinks from the School of Medicine at the University of Cincinnati, and the Division of Clinical Pharmacology and Paediatric Pharmacology Research Unit at the Cincinnati Children’s Hospital Medical Centre, Cincinnati, OH, USA, as well as Associate Professor Noel Cranswick and Associate Professor John Massie from Departments of Respiratory Medicine and Clinical Pharmacology, University of Melbourne and the Murdoch Children’s Research Institute and the Royal Children’s Hospital, Melbourne, VIC, Australia, for the contribution of data from their previous studies in patients with cystic fibrosis. Furthermore, we would like to acknowledge the use of a dataset provided by Professor Leon Aarons (laarons@fs1.pa.man.ac.uk), which was downloaded from the website of the Resource Facility for Population Kinetics (http://depts.washington.edu/rfpk/service/datasets/index.html) [funding source: NIH/NIBIB grant P41-EB01975] and published previously in an original publication (Aarons L, Vozeh S, Wenk M, Weiss P, Follath F. Population pharmacokinetics of tobramycin. Br J Clin Pharmacol. 1989 Sep;28(3):305–14), and Victoria Holden and colleagues at St James’s Hospital in Leeds, UK, for contributing data on children with febrile neutropenia. We also acknowledge support from the following individuals who helped with the data collection and creation of the database: Iona Paterson and Allan Smith, Cystic Fibrosis Unit Pharmacy Department, Gartnavel General Hospital, Glasgow, UK, Sonya Stacey, Royal Children’s Hospital, Brisbane, QLD, Australia. We would like to thank the High Performance Computing Support Group at the University of Queensland (http://www.hpcu.uq.edu.au/hpc/content/view/181/5/) for the support with the NONMEM® installation and the use of the computer facilities.

Author contributions

Dr Hennig had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the pharmacometric data analysis. Authors Hennig, Standing, Staatz and Thomson contributed to study concept and design, acquisition of data, analysis and interpretation of data, drafting of the manuscript and the critical revision of the manuscript for important intellectual content equally.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. School of Pharmacy, University of Queensland, Brisbane, Pharmacy Australia Centre of Excellence (PACE), 20 Cornwall Street, Woolloongabba, QLD 4102, Australia

    Stefanie Hennig & Christine E. Staatz

  2. Department of Pharmaceutical Bioscience, Uppsala University, Uppsala, Sweden

    Stefanie Hennig & Joseph F. Standing

  3. Infectious Diseases and Microbiology Unit, UCL Institute of Child Health, London, UK

    Joseph F. Standing

  4. Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, UK

    Alison H. Thomson

  5. Pharmacy Department, Western Infirmary, Glasgow, UK

    Alison H. Thomson

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  1. Stefanie Hennig
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  2. Joseph F. Standing
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  4. Alison H. Thomson
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Correspondence to Stefanie Hennig.

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Hennig, S., Standing, J.F., Staatz, C.E. et al. Population Pharmacokinetics of Tobramycin in Patients With and Without Cystic Fibrosis. Clin Pharmacokinet 52, 289–301 (2013). https://doi.org/10.1007/s40262-013-0036-y

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