The impact of frailty on pharmacokinetics in older people: using gentamicin population pharmacokinetic modeling to investigate changes in renal drug clearance by glomerular filtration
详细信息 查看全文
- 作者：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) - 关键词：Frailty ; Ageing ; Pharmacokinetics ; Population pharmacokinetics ; Renal clearance ; Glomerular filtration ; Gentamicin
- 刊名：European Journal of Clinical Pharmacology
- 出版年：2014
- 出版时间：May 2014
- 年：2014
- 卷：70
- 期：5
- 页码：549-555
- 全文大小：201 KB
- 参考文献：1. Cerreta F, Eichler HG, Rasi G (2012) Drug policy for an aging population - the European medicines Agency鈥檚 geriatric medicines strategy. New Engl J Med 367(21):1972鈥?974. doi:<span class="a-plus-plus non-url-ref">10.1056/Nejmp1209034 ss="external" href="http://dx.doi.org/10.1056/NEJMp1209034" target="_blank" title="It opens in new window">CrossRef
2. Rockwood K, Mitnitski A (2011) Frailty defined by deficit accumulation and geriatric medicine defined by frailty. Clin Geriatr Med 27(1):17鈥?6. doi:<span class="a-plus-plus non-url-ref">10.1016/J.Cger.2010.08.008 ss="external" href="http://dx.doi.org/10.1016/j.cger.2010.08.008" target="_blank" title="It opens in new window">CrossRef
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鈥?79. doi:<span class="a-plus-plus non-url-ref">10.1111/J.1532-5415.2006.00738.X ss="external" href="http://dx.doi.org/10.1111/j.1532-5415.2006.00738.x" target="_blank" title="It opens in new window">CrossRef
4. Hubbard RE, O鈥橫ahony MS, Woodhouse KW (2013) Medication prescribing in frail older people. Eur J Clin Pharmacol 69(3):319鈥?26. doi:<span class="a-plus-plus non-url-ref">10.1007/S00228-012-1387-2 ss="external" href="http://dx.doi.org/10.1007/s00228-012-1387-2" target="_blank" title="It opens in new window">CrossRef
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鈥?7. doi:<span class="a-plus-plus non-url-ref">10.1093/Gerona/Gls119 ss="external" href="http://dx.doi.org/10.1093/gerona/gls119" target="_blank" title="It opens in new window">CrossRef
6. Hilmer SN (2008) ADME-tox issues for the elderly. Expert Opin Drug Metab Toxicol 4(10):1321鈥?331. doi:<span class="a-plus-plus non-url-ref">10.1517/17425255.4.10.1321 ss="external" href="http://dx.doi.org/10.1517/17425255.4.10.1321" target="_blank" title="It opens in new window">CrossRef
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鈥?92. doi:<span class="a-plus-plus non-url-ref">10.1007/S12603-011-0100-Y ss="external" href="http://dx.doi.org/10.1007/s12603-011-0100-y" target="_blank" title="It opens in new window">CrossRef
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鈥?59. doi:<span class="a-plus-plus non-url-ref">10.1093/Ageing/22.5.354 ss="external" href="http://dx.doi.org/10.1093/ageing/22.5.354" target="_blank" title="It opens in new window">CrossRef
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:<span class="a-plus-plus non-url-ref">10.1038/clpt.201
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鈥?7 ss="external" href="http://dx.doi.org/10.1007/BF02982161" target="_blank" title="It opens in new window">CrossRef
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鈥?81. doi:<span class="a-plus-plus non-url-ref">10.1007/S12603-010-0045-6 ss="external" href="http://dx.doi.org/10.1007/s12603-010-0045-6" target="_blank" title="It opens in new window">CrossRef
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鈥?82. doi:<span class="a-plus-plus non-url-ref">10.1016/J.Clnu.2012.06.012 ss="external" href="http://dx.doi.org/10.1016/j.clnu.2012.06.012" target="_blank" title="It opens in new window">CrossRef
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鈥?55. doi:<span class="a-plus-plus non-url-ref">10.1017/S0714980811000511 ss="external" href="http://dx.doi.org/10.1017/S0714980811000511" target="_blank" title="It opens in new window">CrossRef
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鈥?62
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鈥檚 health and aging studies. J Gerontol a-Biol 61(3):262鈥?66 ss="external" href="http://dx.doi.org/10.1093/gerona/61.3.262" target="_blank" title="It opens in new window">CrossRef
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鈥?37 ss="external" href="http://dx.doi.org/10.1093/gerona/62.7.731" target="_blank" title="It opens in new window">CrossRef
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鈥?89. doi:<span class="a-plus-plus non-url-ref">10.1001/Archinternmed.2007.113 ss="external" href="http://dx.doi.org/10.1001/archinternmed.2007.113" target="_blank" title="It opens in new window">CrossRef
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鈥揗156 ss="external" href="http://dx.doi.org/10.1093/gerona/56.3.M146" target="_blank" title="It opens in new window">CrossRef
19. Gilleard C, Higgs P (2011) Frailty, disability and old age: a re-appraisal. Health 15(5):475鈥?90. doi:<span class="a-plus-plus non-url-ref">10.1177/1363459310383595
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鈥?28. doi:<span class="a-plus-plus non-url-ref">10.1038/Clpt.2011.258 ss="external" href="http://dx.doi.org/10.1038/clpt.2011.258" target="_blank" title="It opens in new window">CrossRef
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鈥?460 ss="external" href="http://dx.doi.org/10.1016/S0047-6374(02)00082-9" target="_blank" title="It opens in new window">CrossRef
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鈥?29. doi:<span class="a-plus-plus non-url-ref">10.1093/ageing/afl041 ss="external" href="http://dx.doi.org/10.1093/ageing/afl041" target="_blank" title="It opens in new window">CrossRef
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鈥?88. doi:<span class="a-plus-plus non-url-ref">10.1111/J.1741-6612.2009.00367.X ss="external" href="http://dx.doi.org/10.1111/j.1741-6612.2009.00367.x" target="_blank" title="It opens in new window">CrossRef
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鈥?35. doi:<span class="a-plus-plus non-url-ref">10.1111/J.1365-2710.2010.01193.X ss="external" href="http://dx.doi.org/10.1111/j.1365-2710.2010.01193.x" target="_blank" title="It opens in new window">CrossRef
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鈥?62. doi:<span class="a-plus-plus non-url-ref">10.1093/Ageing/Afn293 ss="external" href="http://dx.doi.org/10.1093/ageing/afn293" target="_blank" title="It opens in new window">CrossRef
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鈥?31. doi:<span class="a-plus-plus non-url-ref">10.1111/J.1365-2125.2010.03825.X ss="external" href="http://dx.doi.org/10.1111/j.1365-2125.2010.03825.x" target="_blank" title="It opens in new window">CrossRef
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鈥?9. doi:<span class="a-plus-plus non-url-ref">10.1007/Bf01989222 ss="external" href="http://dx.doi.org/10.1007/BF01989222" target="_blank" title="It opens in new window">CrossRef
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鈥?36. doi:<span class="a-plus-plus non-url-ref">10.1016/0893-133x(89)90026-2 ss="external" href="http://dx.doi.org/10.1016/0893-133X(89)90026-2" target="_blank" title="It opens in new window">CrossRef
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鈥檚 lymphomas. Ann Oncol 16(8):1352鈥?358. doi:<span class="a-plus-plus non-url-ref">10.1093/Annonc/Mdi243 ss="external" href="http://dx.doi.org/10.1093/annonc/mdi243" target="_blank" title="It opens in new window">CrossRef
30. Schwartz JB (2006) Erythromycin breath test results in elderly, very elderly, and frail elderly persons. Clin Pharmacol Ther 79(5):440鈥?48. doi:<span class="a-plus-plus non-url-ref">10.1016/J.Clpt.2006.01.006 ss="external" href="http://dx.doi.org/10.1016/j.clpt.2006.01.006" target="_blank" title="It opens in new window">CrossRef
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鈥?24. doi:<span class="a-plus-plus non-url-ref">10.1093/Ageing/19.6.419 ss="external" href="http://dx.doi.org/10.1093/ageing/19.6.419" target="_blank" title="It opens in new window">CrossRef
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鈥?18. doi:<span class="a-plus-plus non-url-ref">10.1093/Ageing/18.6.415 ss="external" href="http://dx.doi.org/10.1093/ageing/18.6.415" target="_blank" title="It opens in new window">CrossRef
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鈥?91. doi:<span class="a-plus-plus non-url-ref">10.1007/Bf00203783 ss="external" href="http://dx.doi.org/10.1007/BF00203783" target="_blank" title="It opens in new window">CrossRef
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鈥?6. doi:<span class="a-plus-plus non-url-ref">10.1111/J.1741-6612.2008.00288.X ss="external" href="http://dx.doi.org/10.1111/j.1741-6612.2008.00288.x" target="_blank" title="It opens in new window">CrossRef
35. Duffull SB, Wright DFB, Winter HR (2011) Interpreting population pharmacokinetic-pharmacodynamic analyses - a clinical viewpoint. Br J Clin Pharmacol 71(6):807鈥?14. doi:<span class="a-plus-plus non-url-ref">10.1111/J.1365-2125.2010.03891.X ss="external" href="http://dx.doi.org/10.1111/j.1365-2125.2010.03891.x" target="_blank" title="It opens in new window">CrossRef
36. Bellanti F, Della Pasqua O (2011) Modelling and simulation as research tools in paediatric drug development. Eur J Clin Pharmacol 67:S75鈥揝86. doi:<span class="a-plus-plus non-url-ref">10.1007/S00228-010-0974-3 ss="external" href="http://dx.doi.org/10.1007/s00228-010-0974-3" target="_blank" title="It opens in new window">CrossRef
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鈥?78 ss="external" href="http://dx.doi.org/10.2174/1389200211209050667" target="_blank" title="It opens in new window">CrossRef
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鈥?211. doi:<span class="a-plus-plus non-url-ref">10.2165/00003088-200342140-00002 ss="external" href="http://dx.doi.org/10.2165/00003088-200342140-00002" target="_blank" title="It opens in new window">CrossRef
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鈥?33. doi:<span class="a-plus-plus non-url-ref">10.1016/J.Jchromb.2012.07.005 ss="external" href="http://dx.doi.org/10.1016/j.jchromb.2012.07.005" target="_blank" title="It opens in new window">CrossRef
40. MIMSOnline (2003) Prescribing Information: DBL Gentamicin Injection BP. In: ed. Health Communication Network
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鈥?30. doi:<span class="a-plus-plus non-url-ref">10.1097/00007691-200310000-00012 ss="external" href="http://dx.doi.org/10.1097/00007691-200310000-00012" target="_blank" title="It opens in new window">CrossRef
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鈥?49. doi:<span class="a-plus-plus non-url-ref">10.1111/J.1445-5994.2011.02452.X ss="external" href="http://dx.doi.org/10.1111/j.1445-5994.2011.02452.x" target="_blank" title="It opens in new window">CrossRef
43. Antibiotic Expert Group (2010) Therapeutic guidelines: antibiotic. Version 14. Therapeutic Guidelines Limited, Melbourne
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鈥?95. doi:<span class="a-plus-plus non-url-ref">10.1016/J.Ijantimicag.2003.07.010 ss="external" href="http://dx.doi.org/10.1016/j.ijantimicag.2003.07.010" target="_blank" title="It opens in new window">CrossRef
45. Devine BJ (1974) Gentamicin therapy. Drug Intel Clin Phar 8(11):650鈥?55
46. Cockcroft DW, Gault MH (1976) Prediction of creatinine clearance from serum creatinine. Nephron 16(1):31鈥?1. doi:<span class="a-plus-plus non-url-ref">10.1159/000180580 ss="external" href="http://dx.doi.org/10.1159/000180580" target="_blank" title="It opens in new window">CrossRef
47. Bland JM, Altman DG (1999) Measuring agreement in method comparison studies. Stat Methods Med Res 8(2):135鈥?60 ss="external" href="http://dx.doi.org/10.1191/096228099673819272" target="_blank" title="It opens in new window">CrossRef
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鈥?83 ss="external" href="http://dx.doi.org/10.1016/0021-9681(87)90171-8" target="_blank" title="It opens in new window">CrossRef
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鈥?38
50. Begg EJ, Barclay ML, Duffull SB (1995) A suggested approach to once-daily aminoglycoside dosing. Br J Clin Pharmacol 39(6):605鈥?09 ss="external" href="http://dx.doi.org/10.1111/j.1365-2125.1995.tb05719.x" target="_blank" title="It opens in new window">CrossRef
51. Beal S, Sheiner LB, Boeckman A (2006) NONMEM User鈥檚 Guides. In: Beal S, Sheiner LB, Boeckman A (Ed). ICON Development Solutions
52. Holford N (2013) Wings for NONMEM, v. 720 for NONMEM 7.2. Available at: http://wfn.sourceforge.net.
53. Janmahasatian S, Duffull SB, Ash S, Ward LC, Byrne NM, Green B (2005) Quantification of lean bodyweight. Clin Pharmacokinet 44(10):1051鈥?065. doi:<span class="a-plus-plus non-url-ref">10.2165/00003088-200544100-00004 ss="external" href="http://dx.doi.org/10.2165/00003088-200544100-00004" target="_blank" title="It opens in new window">CrossRef
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鈥?27. doi:<span class="a-plus-plus non-url-ref">10.1111/J.1365-2125.2009.03586.X ss="external" href="http://dx.doi.org/10.1111/j.1365-2125.2009.03586.x" target="_blank" title="It opens in new window">CrossRef
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鈥?43 ss="external" href="http://dx.doi.org/10.1046/j.1365-2125.1999.00938.x" target="_blank" title="It opens in new window">CrossRef
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鈥揢607 ss="external" href="http://dx.doi.org/10.7326/0003-4819-150-9-200905050-00006" target="_blank" title="It opens in new window">CrossRef
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鈥?50
58. McMurdo MET, Roberts H, Parker S, Wyatt N, May H, Goodman C, Jackson S, Gladman J, O鈥橫ahony 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鈥?65. doi:<span class="a-plus-plus non-url-ref">10.1093/Ageing/Afr115 ss="external" href="http://dx.doi.org/10.1093/ageing/afr115" target="_blank" title="It opens in new window">CrossRef - 作者单位：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. Sydney Medical School, University of Sydney, Sydney, NSW, Australia
2. Department of Clinical Pharmacology and Aged Care and the Kolling Institute of Medical Research, Royal North Shore Hospital, Sydney, NSW, Australia
6. Laboratory of Ageing and Pharmacology, Level 12 Kolling Institute of Medical Research, Royal North Shore Hospital, St Leonards, NSW, 2065, Australia
3. Centre for Education and Research on Aging, Concord RG Hospital, Sydney, NSW, Australia
4. Faculty of Pharmacy, University of Sydney, Sydney, NSW, Australia
5. Centre for Medicine Use and Safety, Monash University, Melbourne, VIC, Australia - ISSN：1432-1041
文摘
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.