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The impact of frailty on pharmacokinetics in older people: using gentamicin population pharmacokinetic modeling to investigate changes in renal drug clearance by glomerular filtration

  • Pharmacokinetics and Disposition
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Abstract

Purpose

Frailty, a multifactorial biological syndrome characterized by a cumulative dysregulation of physiological processes, is associated with changes in pharmacokinetics and pharmacodynamics. The aim of this study was to quantify the effect of frailty on glomerular filtration of drugs, using the probe drug gentamicin.

Methods

Gentamicin concentrations and clinical data including the Reported Edmonton Frail Scale score were pooled from two prospective observational inpatient studies, one on prophylactic gentamicin for urologic surgery and one on therapeutic gentamicin for the empiric treatment of sepsis. Population pharmacokinetic modeling was performed using non-linear mixed effects modeling (NONMEM program) to determine the impact of frailty on gentamicin clearance.

Results

A one-compartment linear pharmacokinetic model best described the data and the addition of frailty to the model reduced the random variability in gentamicin clearance by 12 % after adjustment for renal function (estimated creatinine clearance using lean body weight) and lean body weight. Frail patients had an approximately 12 % lower (bootstrapping results: 14 % median) gentamicin clearance than non-frail patients (calculated as a fractional effect of frailty).

Conclusions

Frailty may independently predict reduced clearance of gentamicin in older patients. Frailty could be considered in the development of dosing guidelines for drugs that undergo significant excretion through glomerular filtration.

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Acknowledgments

We would like to thank the Geoff and Elaine Penney Aging Research Fund for financial support. We would also like to acknowledge Dr. Doug Chesher and PaLMS for the analysis of the drug concentrations; Dr. Kashyap Patel for assistance with the model evaluation; and Ms. Kim Tran, Dr. Patrick Rubie and Dr. Jason Wright for the collection of the prophylactic data.

Conflict of interest

The authors declare no conflicts of interest.

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Authors and Affiliations

  1. Sydney Medical School, University of Sydney, Sydney, NSW, Australia

    Claire Johnston, Sarah N. Hilmer, Slade T. Matthews & Peter R. Carroll

  2. Department of Clinical Pharmacology and Aged Care and the Kolling Institute of Medical Research, Royal North Shore Hospital, Sydney, NSW, Australia

    Claire Johnston, Sarah N. Hilmer & Peter R. Carroll

  3. Centre for Education and Research on Aging, Concord RG Hospital, Sydney, NSW, Australia

    Andrew J. McLachlan

  4. Faculty of Pharmacy, University of Sydney, Sydney, NSW, Australia

    Andrew J. McLachlan

  5. Centre for Medicine Use and Safety, Monash University, Melbourne, VIC, Australia

    Carl M. Kirkpatrick

  6. Laboratory of Ageing and Pharmacology, Level 12 Kolling Institute of Medical Research, Royal North Shore Hospital, St Leonards, NSW, 2065, Australia

    Sarah N. Hilmer

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  1. Claire Johnston
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  2. Sarah N. Hilmer
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  3. Andrew J. McLachlan
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Correspondence to Sarah N. Hilmer.

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Johnston, C., Hilmer, S.N., McLachlan, A.J. et al. The impact of frailty on pharmacokinetics in older people: using gentamicin population pharmacokinetic modeling to investigate changes in renal drug clearance by glomerular filtration. Eur J Clin Pharmacol 70, 549–555 (2014). https://doi.org/10.1007/s00228-014-1652-7

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