Display options
Cite
Soejima K, Sato H, Hisaka A. Age-Related Change in Hepatic Clearance Inferred from Multiple Population Pharmacokinetic Studies: Comparison with Renal Clearance and Their Associations with Organ Weight and Blood Flow. Clin Pharmacokinet. 2021;doi: 10.1007/s40262-021-01069-z.
Soejima, K., Sato, H., & Hisaka, A. (2021). Age-Related Change in Hepatic Clearance Inferred from Multiple Population Pharmacokinetic Studies: Comparison with Renal Clearance and Their Associations with Organ Weight and Blood Flow. Clinical pharmacokinetics, . https://doi.org/10.1007/s40262-021-01069-z
Soejima, Kuretake, et al. "Age-Related Change in Hepatic Clearance Inferred from Multiple Population Pharmacokinetic Studies: Comparison with Renal Clearance and Their Associations with Organ Weight and Blood Flow." Clinical pharmacokinetics vol. (2021). doi: https://doi.org/10.1007/s40262-021-01069-z
Soejima K, Sato H, Hisaka A. Age-Related Change in Hepatic Clearance Inferred from Multiple Population Pharmacokinetic Studies: Comparison with Renal Clearance and Their Associations with Organ Weight and Blood Flow. Clin Pharmacokinet. 2021 Sep 13; doi: 10.1007/s40262-021-01069-z. Epub 2021 Sep 13. PMID: 34514537.
Copy Download .nbib Format: NLM
Share it on

Clin Pharmacokinet. 2021 Sep 13; doi: 10.1007/s40262-021-01069-z. Epub 2021 Sep 13.

Age-Related Change in Hepatic Clearance Inferred from Multiple Population Pharmacokinetic Studies: Comparison with Renal Clearance and Their Associations with Organ Weight and Blood Flow.

Clinical pharmacokinetics

Kuretake Soejima, Hiromi Sato, Akihiro Hisaka

Affiliations

  1. Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba-shi, Chiba, 260-8675, Japan.
  2. Bristol-Myers Squibb K.K., 6-5-1 Nishishinjuku, Shinjuku-ku, Tokyo, 163-1328, Japan.
  3. Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba-shi, Chiba, 260-8675, Japan. [email protected].

PMID: 34514537 DOI: 10.1007/s40262-021-01069-z

Abstract

OBJECTIVE: This study aimed to examine the magnitude of age-related change in hepatic clearance by integrating the data of multiple drugs and to compare this with renal clearance, considering associations with age-related changes in organ weight and blood flow.

METHODS: The results of multiple population pharmacokinetic analyses that detected age-related clearance changes in hepatically eliminated drugs were collected. The relationship between hepatic clearance of the unbound drug and age was then analyzed using the nonlinear least-squares method, adjusting for interdrug differences. The obtained change in hepatic clearance was compared with age-related changes in liver weight and hepatic blood flow in Japanese and Westerners. For comparison, the changes in renal clearance were analyzed similarly.

RESULTS: In total, 18 drugs were analyzed. The hepatic unbound clearance decreased by 32% at age 80 years and by 40% at age 90 years, compared with age 40 years, suggesting that it decreased by 0.80% per year with aging. The rate of the decrease was consistent with decreases in hepatic weight per person or blood flow per person, regardless of ethnicity and sex. Since age-related change in body weight varied somewhat by sex or ethnicity, hepatic weight per body weight was less consistent to account for age-related change in hepatic clearance. As for an index of renal clearance, the changes in inulin clearance with age were similar to those in renal blood flow, with a decrease of 0.97% per year from the age of 40 years.

CONCLUSIONS: Hepatic clearance consistently decreased by 0.80% per year from the age of 40 years, with aging for multiple drugs analyzed in this study. Changes in organ weight and blood flow are considered to be primarily responsible for the age-related changes in hepatic and renal clearance.

© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.

References

  1. United Nations, Department of Economic and Social Affairs, Population Division (2019) World population prospects 2019, Volume II: demographic profiles (ST/ESA/SER.A/427). Available at: https://population.un.org/wpp/Publications/Files/WPP2019_Volume-II-Demographic-Profiles.pdf . Accessed 23 Oct 2020. - PubMed
  2. Charlesworth CJ, Smit E, Lee DS, Alramadhan F, Odden MC. Polypharmacy among adults aged 65 years and older in the United States: 1988–2010. J Gerontol A Biol Sci Med Sci. 2015;70(8):989–95. - PubMed
  3. Pouyanne P, Haramburu F, Imbs JL, Bégaud B. Admissions to hospital caused by adverse drug reactions: cross sectional incidence study. French Pharmacovigilance Centres. BMJ. 2000;320(7241):1036. - PubMed
  4. Bordet R, Gautier S, Le Louet H, Dupuis B, Caron J. Analysis of the direct cost of adverse drug reactions in hospitalised patients. Eur J Clin Pharmacol. 2001;56(12):935–41. - PubMed
  5. Alhawassi TM, Krass I, Bajorek BV, Pont LG. A systematic review of the prevalence and risk factors for adverse drug reactions in the elderly in the acute care setting. Clin Interv Aging. 2014;9:2079–86. - PubMed
  6. Davies EA, O’Mahony MS. Adverse drug reactions in special populations—the elderly. Br J Clin Pharmacol. 2015;80(4):796–807. - PubMed
  7. Ayalew MB, Tegegn HG, Abdela OA. Drug related hospital admissions; a systematic review of the recent literatures. Bull Emerg Trauma. 2019;7(4):339–46. - PubMed
  8. International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use. ICH topic E7—studies in support of special populations: geriatrics. 1994. Available at: https://database.ich.org/sites/default/files/E7_Guideline.pdf . Accessed 23 Oct 2020. - PubMed
  9. Davies DF, Shock NW. Age changes in glomerular filtration rate, effective renal plasma flow, and tubular excretory capacity in adult males. J Clin Investig. 1950;29(5):496–507. - PubMed
  10. Horio M, Yasuda Y, Kaimori J, Ichimaru N, Isaka Y, Takahara S, et al. Performance of the Japanese GFR equation in potential kidney donors. Clin Exp Nephrol. 2012;16(3):415–20. - PubMed
  11. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16(1):31–41. - PubMed
  12. Giusti DL, Hayton WL. Dosage regimen adjustments in renal impairment. Drug Intell Clin Pharm. 1973;7(9):382–7. - PubMed
  13. Simonsen O, Grubb A, Thysell H. The blood serum concentration of cystatin C (gamma-trace) as a measure of the glomerular filtration rate. Scand J Clin Lab Invest. 1985;45(2):97–101. - PubMed
  14. Shimada T, Yamazaki H, Mimura M, Inui Y, Guengerich FP. Interindividual variations in human liver cytochrome P-450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals: studies with liver microsomes of 30 Japanese and 30 Caucasians. J Pharmacol Exp Ther. 1994;270(1):414–23. - PubMed
  15. Parkinson A, Mudra DR, Johnson C, Dwyer A, Carroll KM. The effects of gender, age, ethnicity, and liver cirrhosis on cytochrome P450 enzyme activity in human liver microsomes and inducibility in cultured human hepatocytes. Toxicol Appl Pharmacol. 2004;199(3):193–209. - PubMed
  16. Achour B, Barber J, Rostami-Hodjegan A. Expression of hepatic drug-metabolizing cytochrome p450 enzymes and their intercorrelations: a meta-analysis. Drug Metab Dispos. 2014;42(8):1349–56. - PubMed
  17. Achour B, Russell MR, Barber J, Rostami-Hodjegan A. Simultaneous quantification of the abundance of several cytochrome P450 and uridine 5ʹ-diphospho-glucuronosyltransferase enzymes in human liver microsomes using multiplexed targeted proteomics. Drug Metab Dispos. 2014;42(4):500–10. - PubMed
  18. Stader F, Siccardi M, Battegay M, Kinvig H, Penny MA, Marzolini C. Repository describing an aging population to inform physiologically based pharmacokinetic models considering anatomical, physiological, and biological age-dependent changes. Clin Pharmacokinet. 2019;58(4):483–501. - PubMed
  19. Veering BT, Burm AG, Souverijn JH, Serree JM, Spierdijk J. The effect of age on serum concentrations of albumin and alpha 1-acid glycoprotein. Br J Clin Pharmacol. 1990;29(2):201–6. - PubMed
  20. Le Couteur DG, McLean AJ. The aging liver. Drug clearance and an oxygen diffusion barrier hypothesis. Clin Pharmacokinet. 1998;34(5):359–73. - PubMed
  21. Mould DR, Upton RN. Basic concepts in population modeling, simulation, and model-based drug development—part 2: introduction to pharmacokinetic modeling methods. CPT Pharmacometr Syst Pharmacol. 2013;2(4):e38. - PubMed
  22. Bhattaram VA, Booth BP, Ramchandani RP, Beasley BN, Wang Y, Tandon V, et al. Impact of pharmacometrics on drug approval and labeling decisions: a survey of 42 new drug applications. AAPS J. 2005;7(3):E503–12. - PubMed
  23. Lee JY, Garnett CE, Gobburu JV, Bhattaram VA, Brar S, Earp JC, et al. Impact of pharmacometric analyses on new drug approval and labelling decisions: a review of 198 submissions between 2000 and 2008. Clin Pharmacokinet. 2011;50(10):627–35. - PubMed
  24. Wählby U, Jonsson EN, Karlsson MO. Assessment of actual significance levels for covariate effects in NONMEM. J Pharmacokinet Pharmacodyn. 2001;28(3):231–52. - PubMed
  25. Mould DR, Upton RN. Basic concepts in population modeling, simulation, and model-based drug development. CPT Pharmacometr Syst Pharmacol. 2012;1(9):e6. - PubMed
  26. Winter ME. Basic clinical pharmacokinetics. 5th ed. Wolters Kluwer/Lippincott Williams & Wilkins; 2010. - PubMed
  27. Medical Tribune Inc. Drugs involved in significant pharmacokinetic drug–drug interactions in 2019. Pharma Tribune. Available at: https://ptweb.jp/images/asset/PT_DDI_2019_Eng_0219.pdf . Accessed 23 Oct 2020. - PubMed
  28. Iwatsubo T, Hirota N, Ooie T, Suzuki H, Sugiyama Y. Prediction of in vivo drug disposition from in vitro data based on physiological pharmacokinetics. Biopharm Drug Dispos. 1996;17(4):273–310. - PubMed
  29. Roberts MS, Rowland M. A dispersion model of hepatic elimination: 1. Formulation of the model and bolus considerations. J Pharmacokinet Biopharm. 1986;14(3):227–60. - PubMed
  30. Bricker NS, Morrin PA, Kime SW Jr. The pathologic physiology of chronic Bright’s disease. An exposition of the “intact nephron hypothesis.” Am J Med. 1960;28:77–98. - PubMed
  31. Planning and Investigation Committee of the Japanese Society of Legal Medicine. Weights and sizes of internal organs measured in forensic autopsy cases from 2009 to 2013 in Japan. Questionnaire research performed by the Japanese Society of Legal Medicine. 2015. - PubMed
  32. Schlender JF, Meyer M, Thelen K, Krauss M, Willmann S, Eissing T, et al. Development of a whole-body physiologically based pharmacokinetic approach to assess the pharmacokinetics of drugs in elderly individuals. Clin Pharmacokinet. 2016;55(12):1573–89. - PubMed
  33. Wynne HA, Cope LH, Mutch E, Rawlins MD, Woodhouse KW, James OF. The effect of age upon liver volume and apparent liver blood flow in healthy man. Hepatology. 1989;9(2):297–301. - PubMed
  34. Holmberg L, Odar-Cederlöf I, Boréus LO, Heyner L, Ehrnebo M. Comparative disposition of pethidine and norpethidine in old and young patients. Eur J Clin Pharmacol. 1982;22(2):175–9. - PubMed
  35. Owen JA, Sitar DS, Berger L, Brownell L, Duke PC, Mitenko PA. Age-related morphine kinetics. Clin Pharmacol Ther. 1983;34(3):364–8. - PubMed
  36. Baillie SP, Bateman DN, Coates PE, Woodhouse KW. Age and the pharmacokinetics of morphine. Age Ageing. 1989;18(4):258–62. - PubMed
  37. Abernethy DR, Schwartz JB, Todd EL, Luchi R, Snow E. Verapamil pharmacodynamics and disposition in young and elderly hypertensive patients Altered electrocardiographic and hypotensive responses. Ann Intern Med. 1986;105(3):329–36. - PubMed
  38. Abernethy DR, Greenblatt DJ, Shader RI. Imipramine and desipramine disposition in the elderly. J Pharmacol Exp Ther. 1985;232(1):183–8. - PubMed
  39. Abernethy DR, Greenblatt DJ. Impairment of lidocaine clearance in elderly male subjects. J Cardiovasc Pharmacol. 1983;5(6):1093–6. - PubMed
  40. Antal EJ, Kramer PA, Mercik SA, Chapron DJ, Lawson IR. Theophylline pharmacokinetics in advanced age. Br J Clin Pharmacol. 1981;12(5):637–45. - PubMed
  41. Au WY, Dutt AK, DeSoyza N. Theophylline kinetics in chronic obstructive airway disease in the elderly. Clin Pharmacol Ther. 1985;37(4):472–8. - PubMed
  42. Vestal RE, Cusack BJ, Mercer GD, Dawson GW, Park BK. Aging and drug interactions. I. Effect of cimetidine and smoking on the oxidation of theophylline and cortisol in healthy men. J Pharmacol Exp Ther. 1987;241(2):488–500. - PubMed
  43. Greenblatt DJ, Divoll M, Abernethy DR, Harmatz JS, Shader RI. Antipyrine kinetics in the elderly: prediction of age-related changes in benzodiazepine oxidizing capacity. J Pharmacol Exp Ther. 1982;220(1):120–6. - PubMed
  44. Shepherd AM, Hewick DS, Moreland TA, Stevenson IH. Age as a determinant of sensitivity to warfarin. Br J Clin Pharmacol. 1977;4(3):315–20. - PubMed
  45. Schwartz JB, Abernethy DR. Responses to intravenous and oral diltiazem in elderly and younger patients with systemic hypertension. Am J Cardiol. 1987;59(12):1111–7. - PubMed
  46. Greenblatt DJ, Abernethy DR, Matlis R, Harmatz JS, Shader RI. Absorption and disposition of ibuprofen in the elderly. Arthritis Rheum. 1984;27(9):1066–9. - PubMed
  47. Castleden CM, George CF. The effect of ageing on the hepatic clearance of propranolol. Br J Clin Pharmacol. 1979;7(1):49–54. - PubMed
  48. Gupta SK, Atkinson L, Tu T, Longstreth JA. Age and gender related changes in stereoselective pharmacokinetics and pharmacodynamics of verapamil and norverapamil. Br J Clin Pharmacol. 1995;40(4):325–31. - PubMed
  49. Polasek TM, Patel F, Jensen BP, Sorich MJ, Wiese MD, Doogue MP. Predicted metabolic drug clearance with increasing adult age. Br J Clin Pharmacol. 2013;75(4):1019–28. - PubMed
  50. Sotaniemi EA, Arranto AJ, Pelkonen O, Pasanen M. Age and cytochrome P450-linked drug metabolism in humans: an analysis of 226 subjects with equal histopathologic conditions. Clin Pharmacol Ther. 1997;61(3):331–9. - PubMed
  51. Butler JM, Begg EJ. Free drug metabolic clearance in elderly people. Clin Pharmacokinet. 2008;47(5):297–321. - PubMed
  52. Greenblatt DJ, Allen MD, Harmatz JS, Shader RI. Diazepam disposition determinants. Clin Pharmacol Ther. 1980;27(3):301–12. - PubMed
  53. Perucca E, Grimaldi R, Gatti G, Pirracchio S, Crema F, Frigo GM. Pharmacokinetics of valproic acid in the elderly. Br J Clin Pharmacol. 1984;17(6):665–9. - PubMed
  54. Wilkinson GR, Shand DG. Commentary: a physiological approach to hepatic drug clearance. Clin Pharmacol Ther. 1975;18(4):377–90. - PubMed

Publication Types

Grant support