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



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.


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.


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).


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.


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)


  1. 1.
    Cerreta F, Eichler HG, Rasi G (2012) Drug policy for an aging population - the European medicines Agency’s geriatric medicines strategy. New Engl J Med 367(21):1972–1974. doi:10.1056/Nejmp1209034 PubMedCrossRefGoogle Scholar
  2. 2.
    Rockwood K, Mitnitski A (2011) Frailty defined by deficit accumulation and geriatric medicine defined by frailty. Clin Geriatr Med 27(1):17–26. doi:10.1016/J.Cger.2010.08.008 PubMedCrossRefGoogle Scholar
  3. 3.
    Rockwood K, Mitnitski A, Song XW, Steen B, Skoog I (2006) Long-term risks of death and institutionalization of elderly people in relation to deficit accumulation at age 70. J Am Geriatr Soc 54(6):975–979. doi:10.1111/J.1532-5415.2006.00738.X PubMedCrossRefGoogle Scholar
  4. 4.
    Hubbard RE, O’Mahony MS, Woodhouse KW (2013) Medication prescribing in frail older people. Eur J Clin Pharmacol 69(3):319–326. doi:10.1007/S00228-012-1387-2 PubMedCrossRefGoogle Scholar
  5. 5.
    Rodriguez-Manas L, Feart C, Mann G, Vina J, Chatterji S, Chodzko-Zajko W, Harmand MGC, Bergman H, Carcaillon L, Nicholson C, Scuteri A, Sinclair A, Pelaez M, Van der Cammen T, Beland F, Bickenbach J, Delamarche P, Ferrucci L, Fried LP, Gutierrez-Robledo LM, Rockwood K, Artalejo FR, Serviddio G, Vega E, Grp F-C (2013) Searching for an operational definition of frailty: a Delphi method based consensus statement. The frailty operative definition-consensus conference project. J Gerontol A Biol 68(1):62–67. doi:10.1093/Gerona/Gls119 CrossRefGoogle Scholar
  6. 6.
    Hilmer SN (2008) ADME-tox issues for the elderly. Expert Opin Drug Metab Toxicol 4(10):1321–1331. doi:10.1517/17425255.4.10.1321 PubMedCrossRefGoogle Scholar
  7. 7.
    Mitchell SJ, Hilmer SN, Kirkpatrick CMJ, Hansen RD, Williamson DA, Singh NA, Finnegan TP, Allen BJ, Diamond TH, Diwan AD, Lloyd BD, Smith EUR, Singh MAF (2012) Estimation of lean body weight in older women with hip fracture. J Nutr Health Aging 16(2):188–192. doi:10.1007/S12603-011-0100-Y PubMedCrossRefGoogle Scholar
  8. 8.
    Wynne HA, Yelland C, Cope LH, Boddy A, Woodhouse KW, Bateman DN (1993) The association-of-Age-and-frailty with the pharmacokinetics and pharmacodynamics of metoclopramide. Age Ageing 22(5):354–359. doi:10.1093/Ageing/22.5.354 PubMedCrossRefGoogle Scholar
  9. 9.
    Johnston C, Kirkpatrick CMJ, McLachlan AJ, Hilmer SN (2012) Physiologically based pharmacokinetic modelling at the extremes of age. Clin Pharmacol Ther 93(2):148. doi:10.1038/clpt.201 Google Scholar
  10. 10.
    Van Kan GA, Rolland Y, Bergman H, Morley JE, Kritchevsky SB, Vellas B, Panel GA (2008) The IANA task force on frailty assessment of older people in clinical practice. J Nutr Health Aging 12(1):29–37CrossRefGoogle Scholar
  11. 11.
    Gobbens RJJ, Luijkx KG, Wijnen-Sponselee MT, Schols JMGA (2010) Towards an integral conceptual model of frailty. J Nutr Health Aging 14(3):175–181. doi:10.1007/S12603-010-0045-6 PubMedCrossRefGoogle Scholar
  12. 12.
    Fearon KCH (2012) The 2011 ESPEN arvid wretlind lecture: cancer cachexia: the potential impact of translational research on patient-focused outcomes. Clin Nutr 31(5):577–582. doi:10.1016/J.Clnu.2012.06.012 PubMedCrossRefGoogle Scholar
  13. 13.
    Au A, Puts MTE, Fletcher JD, Sourial N, Bergman H (2011) Frailty markers predicting emergency department visits in a community-dwelling sample of vulnerable seniors in Montreal. Can J Aging 30(4):647–655. doi:10.1017/S0714980811000511 PubMedCrossRefGoogle Scholar
  14. 14.
    Avila-Funes JA, Aguilar-Navarro S, Melano-Carranza E (2008) Frailty, an enigmatic and controversial concept in geriatrics. The biological perspective. Gac Med Mex 144(3):255–262PubMedGoogle Scholar
  15. 15.
    Bandeen-Roche K, Xue QL, Ferrucci L, Walston J, Guralnik JM, Chaves P, Zeger SL, Fried LP (2006) Phenotype of frailty: characterization in the women’s health and aging studies. J Gerontol a-Biol 61(3):262–266CrossRefGoogle Scholar
  16. 16.
    Bergman H, Ferrucci L, Guralnik J, Hogan DB, Hummel S, Karunananthan S, Wolfson C (2007) Frailty: an emerging research and clinical paradigm - issues and controversies. J Gerontol A Biol 62(7):731–737CrossRefGoogle Scholar
  17. 17.
    Ensrud KE, Ewing SK, Taylor BC, Fink HA, Cawthon PM, Stone KL, Hillier TA, Cauley JA, Hochberg MC, Rodondi N, Tracy JK, Cummings SR, Sofr G (2008) Comparison of 2 frailty indexes for prediction of falls, disability, fractures, and death in older women. Arch Intern Med 168(4):382–389. doi:10.1001/Archinternmed.2007.113 PubMedCrossRefGoogle Scholar
  18. 18.
    Fried LP, Tangen CM, Walston J, Newman AB, Hirsch C, Gottdiener J, Seeman T, Tracy R, Kop WJ, Burke G, McBurnie MA, Collabor CHS (2001) Frailty in older adults: evidence for a phenotype. J Gerontol A Biol 56(3):M146–M156CrossRefGoogle Scholar
  19. 19.
    Gilleard C, Higgs P (2011) Frailty, disability and old age: a re-appraisal. Health 15(5):475–490. doi:10.1177/1363459310383595 PubMedGoogle Scholar
  20. 20.
    Gnjidic D, Hilmer SN, Blyth FM, Naganathan V, Cumming RG, Handelsman DJ, McLachlan AJ, Abernethy DR, Banks E, Le Couteur DG (2012) High-risk prescribing and incidence of frailty among older community-dwelling men. Clin Pharmacol Ther 91(3):521–528. doi:10.1038/Clpt.2011.258 PubMedCrossRefGoogle Scholar
  21. 21.
    Mitnitski AB, Mogilner AJ, MacKnight C, Rockwood K (2002) The mortality rate as a function of accumulated deficits in a frailty index. Mech Ageing Dev 123(11):1457–1460PubMedCrossRefGoogle Scholar
  22. 22.
    Rolfson DB, Majumdar SR, Tsuyuki RT, Tahir A, Rockwood K (2006) Validity and reliability of the edmonton frail scale. Age Ageing 35(5):526–529. doi:10.1093/ageing/afl041 PubMedCrossRefGoogle Scholar
  23. 23.
    Hilmer SN, Perera V, Mitchell S, Murnion BP, Dent J, Bajorek B, Matthews S, Rolfson DB (2009) The assessment of frailty in older people in acute care. Australas J Ageing 28(4):182–188. doi:10.1111/J.1741-6612.2009.00367.X PubMedCrossRefGoogle Scholar
  24. 24.
    Mitchell SJ, Hilmer SN, Murnion BP, Matthews S (2011) Hepatotoxicity of therapeutic short-course paracetamol in hospital inpatients: impact of ageing and frailty. J Clin Pharma Ther 36(3):327–335. doi:10.1111/J.1365-2710.2010.01193.X CrossRefGoogle Scholar
  25. 25.
    Perera V, Bajorek BV, Matthews S, Hilmer SN (2009) The impact of frailty on the utilisation of antithrombotic therapy in older patients with atrial fibrillation. Age Ageing 38(2):156–162. doi:10.1093/Ageing/Afn293 PubMedCrossRefGoogle Scholar
  26. 26.
    Hilmer SN, Tran K, Rubie P, Wright J, Gnjidic D, Mitchell SJ, Matthews S, Carroll PR (2011) Gentamicin pharmacokinetics in old age and frailty. Br J Clin Pharmacol 71(2):224–231. doi:10.1111/J.1365-2125.2010.03825.X PubMedCentralPubMedCrossRefGoogle Scholar
  27. 27.
    Janknegt R, Boogaardvandenborn J, Hameleers BAMJ, Hooymans PM, Rang J, Smits CAM, Willemsthissen ME (1992) Pharmacokinetics of amoxicillin in elderly inpatients. Pharm Weekblad 14(1):27–29. doi:10.1007/Bf01989222 CrossRefGoogle Scholar
  28. 28.
    Katz IR, Simpson GM, Jethanandani V, Cooper T, Muhly C (1989) Steady-state pharmacokinetics of nortriptyline in the frail elderly. Neuropsychopharmacol: Off Publ Am Coll Neuropsychopharmacol 2(3):229–236. doi:10.1016/0893-133x(89)90026-2 CrossRefGoogle Scholar
  29. 29.
    Monfardini S, Aversa SML, Zoli V, Salvagno L, Bianco A, Bordonaro R, Benevolo G, Crugnola M, Crivellari G, Vivaldi P, Basso U, Torri V, NHLCSG (2005) Vinorelbine and prednisone in frail elderly patients with intermediate-high grade non-Hodgkin’s lymphomas. Ann Oncol 16(8):1352–1358. doi:10.1093/Annonc/Mdi243 PubMedCrossRefGoogle Scholar
  30. 30.
    Schwartz JB (2006) Erythromycin breath test results in elderly, very elderly, and frail elderly persons. Clin Pharmacol Ther 79(5):440–448. doi:10.1016/J.Clpt.2006.01.006 PubMedCrossRefGoogle Scholar
  31. 31.
    Wynne HA, Cope LH, Herd B, Rawlins MD, James OFW, Woodhouse KW (1990) The association of Age and frailty with paracetamol conjugation in man. Age Ageing 19(6):419–424. doi:10.1093/Ageing/19.6.419 PubMedCrossRefGoogle Scholar
  32. 32.
    Wynne HA, Cope LH, James OFW, Rawlins MD, Woodhouse KW (1989) The effect of age and frailty upon acetanilide clearance in man. Age Ageing 18(6):415–418. doi:10.1093/Ageing/18.6.415 PubMedCrossRefGoogle Scholar
  33. 33.
    Zeeh J, Fuchs L, Bergmann W, Antonin KH, Degel F, Bieck P, Platt D (1996) Influence of age, frailty and liver function on the pharmacokinetics of brofaromine. Eur J Clin Pharmacol 49(5):387–391. doi:10.1007/Bf00203783 PubMedCrossRefGoogle Scholar
  34. 34.
    Ridda I, Lindley R, MacIntyre RC (2008) The challenges of clinical trials in the exclusion zone: the case of the frail elderly. Australas J Ageing 27(2):61–66. doi:10.1111/J.1741-6612.2008.00288.X PubMedCrossRefGoogle Scholar
  35. 35.
    Duffull SB, Wright DFB, Winter HR (2011) Interpreting population pharmacokinetic-pharmacodynamic analyses - a clinical viewpoint. Br J Clin Pharmacol 71(6):807–814. doi:10.1111/J.1365-2125.2010.03891.X PubMedCentralPubMedCrossRefGoogle Scholar
  36. 36.
    Bellanti F, Della Pasqua O (2011) Modelling and simulation as research tools in paediatric drug development. Eur J Clin Pharmacol 67:S75–S86. doi:10.1007/S00228-010-0974-3 CrossRefGoogle Scholar
  37. 37.
    Perera V, Gross AS, McLachlan AJ (2012) Measurement of CYP1A2 activity: a focus on caffeine as a probe. Curr Drug Metab 13(5):667–678PubMedCrossRefGoogle Scholar
  38. 38.
    Tett SE, Kirkpatrick CM, Gross AS, McLachlan AJ (2003) Principles and clinical application of assessing alterations in renal elimination pathways. Clin Pharmacokinet 42(14):1193–1211. doi:10.2165/00003088-200342140-00002 PubMedCrossRefGoogle Scholar
  39. 39.
    Ghassabian S, Moosavi SM, Valero YG, Shekar K, Fraser JF, Smith MT (2012) High-throughput assay for simultaneous quantification of the plasma concentrations of morphine, fentanyl, midazolam and their major metabolites using automated SPE coupled to LC-MS/MS. J Chromatogr B 903:126–133. doi:10.1016/J.Jchromb.2012.07.005 CrossRefGoogle Scholar
  40. 40.
    MIMSOnline (2003) Prescribing Information: DBL Gentamicin Injection BP. In: ed. Health Communication NetworkGoogle Scholar
  41. 41.
    Kirkpatrick CMJ, Duffull SB, Begg EJ, Frampton C (2003) The use of a change in gentamicin clearance as an early predictor of gentamicin-induced nephrotoxicity. Ther Drug Monit 25(5):623–630. doi:10.1097/00007691-200310000-00012 PubMedCrossRefGoogle Scholar
  42. 42.
    Avent ML, Rogers BA, Cheng AC, Paterson DL (2011) Current use of aminoglycosides: indications, pharmacokinetics and monitoring for toxicity. Intern Med J 41(6):441–449. doi:10.1111/J.1445-5994.2011.02452.X PubMedCrossRefGoogle Scholar
  43. 43.
    Antibiotic Expert Group (2010) Therapeutic guidelines: antibiotic. Version 14. Therapeutic Guidelines Limited, MelbourneGoogle Scholar
  44. 44.
    Xuan DW, Nicolau DP, Nightingale CH (2004) Population pharmacokinetics of gentamicin in hospitalized patients receiving once-daily dosing. Int J Antimicrob Agents 23(3):291–295. doi:10.1016/J.Ijantimicag.2003.07.010 PubMedCrossRefGoogle Scholar
  45. 45.
    Devine BJ (1974) Gentamicin therapy. Drug Intel Clin Phar 8(11):650–655Google Scholar
  46. 46.
    Cockcroft DW, Gault MH (1976) Prediction of creatinine clearance from serum creatinine. Nephron 16(1):31–41. doi:10.1159/000180580 PubMedCrossRefGoogle Scholar
  47. 47.
    Bland JM, Altman DG (1999) Measuring agreement in method comparison studies. Stat Methods Med Res 8(2):135–160PubMedCrossRefGoogle Scholar
  48. 48.
    Charlson ME, Pompei P, Ales KL, MacKenzie CR (1987) A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis 40(5):373–383PubMedCrossRefGoogle Scholar
  49. 49.
    Levy MM, Fink MP, Marshall JC, Abraham E, Angus D, Cook D, Cohen J, Opal SM, Vincent JL, Ramsay G (2003) International Sepsis Definitions Conference. In: SCCM/ESICM/ACCP/ATS/SISed. Intens Care Med 29(4):530–538Google Scholar
  50. 50.
    Begg EJ, Barclay ML, Duffull SB (1995) A suggested approach to once-daily aminoglycoside dosing. Br J Clin Pharmacol 39(6):605–609PubMedCentralPubMedCrossRefGoogle Scholar
  51. 51.
    Beal S, Sheiner LB, Boeckman A (2006) NONMEM User’s Guides. In: Beal S, Sheiner LB, Boeckman A (Ed). ICON Development SolutionsGoogle Scholar
  52. 52.
    Holford N (2013) Wings for NONMEM, v. 720 for NONMEM 7.2. Available at: Scholar
  53. 53.
    Janmahasatian S, Duffull SB, Ash S, Ward LC, Byrne NM, Green B (2005) Quantification of lean bodyweight. Clin Pharmacokinet 44(10):1051–1065. doi:10.2165/00003088-200544100-00004 PubMedCrossRefGoogle Scholar
  54. 54.
    Mitchell SJ, Kirkpatrick CMJ, Le Couteur DG, Naganathan V, Sambrook PN, Seibel MJ, Blyth FM, Waite LM, Handelsman DJ, Cumming RG, Hilmer SN (2010) Estimation of lean body weight in older community-dwelling men. Br J Clin Pharmacol 69(2):118–127. doi:10.1111/J.1365-2125.2009.03586.X PubMedCentralPubMedCrossRefGoogle Scholar
  55. 55.
    Kirkpatrick CMJ, Duffull SB, Begg EJ (1999) Pharmacokinetics of gentamicin in 957 patients with varying renal function dosed once daily. Br J Clin Pharmacol 47(6):637–643PubMedCentralPubMedCrossRefGoogle Scholar
  56. 56.
    Levey AS, Stevens LA, Schmid CH, Zhang YP, Castro AF, Feldman HI, Kusek JW, Eggers P, Van Lente F, Greene T, Coresh J, Co CKDE (2009) A new equation to estimate glomerular filtration rate. Ann Intern Med 150(9):604–U607PubMedCentralPubMedCrossRefGoogle Scholar
  57. 57.
    Balik M, Sedivy J, Waldauf P, Kolar M, Smejkalova V, Pachl J (2005) Can bioimpedance determine the volume of distribution of antibiotics in sepsis? Anaesth Intens Care 33(3):345–350Google Scholar
  58. 58.
    McMurdo MET, Roberts H, Parker S, Wyatt N, May H, Goodman C, Jackson S, Gladman J, O’Mahony S, Ali K, Dickinson E, Edison P, Dyer C, Network CCR (2011) Improving recruitment of older people to research through good practice. Age Ageing 40(6):659–665. doi:10.1093/Ageing/Afr115 PubMedCrossRefGoogle Scholar

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

Personalised recommendations