European Journal of Clinical Pharmacology

, Volume 70, Issue 5, pp 549–555

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

  • Claire Johnston
  • Sarah N. Hilmer
  • Andrew J. McLachlan
  • Slade T. Matthews
  • Peter R. Carroll
  • Carl M. Kirkpatrick
Pharmacokinetics and Disposition

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.

Keywords

Frailty Ageing Pharmacokinetics Population pharmacokinetics Renal clearance Glomerular filtration Gentamicin 

Supplementary material

228_2014_1652_MOESM1_ESM.docx (253 kb)
Supplementary material(DOCX 253 kb)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Claire Johnston
    • 1
    • 2
  • Sarah N. Hilmer
    • 1
    • 2
    • 6
  • Andrew J. McLachlan
    • 3
    • 4
  • Slade T. Matthews
    • 1
  • Peter R. Carroll
    • 1
    • 2
  • Carl M. Kirkpatrick
    • 5
  1. 1.Sydney Medical SchoolUniversity of SydneySydneyAustralia
  2. 2.Department of Clinical Pharmacology and Aged Care and the Kolling Institute of Medical ResearchRoyal North Shore HospitalSydneyAustralia
  3. 3.Centre for Education and Research on AgingConcord RG HospitalSydneyAustralia
  4. 4.Faculty of PharmacyUniversity of SydneySydneyAustralia
  5. 5.Centre for Medicine Use and SafetyMonash UniversityMelbourneAustralia
  6. 6.Laboratory of Ageing and Pharmacology, Level 12 Kolling Institute of Medical ResearchRoyal North Shore HospitalSt LeonardsAustralia

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