The AAPS Journal

, Volume 19, Issue 2, pp 551–556 | Cite as

Pharmacokinetics and Saturable Absorption of Gabapentin in Nursing Home Elderly Patients

  • Ghada F. Ahmed
  • Sai Praneeth R. Bathena
  • Richard C. Brundage
  • Ilo E. Leppik
  • Jeannine M. Conway
  • Janice B. Schwartz
  • Angela K. Birnbaum
Research Article

Abstract

Pharmacokinetic data of gabapentin (GBP) in community-dwelling elderly patients show a significant effect of advanced age on GBP pharmacokinetics due to altered renal function. However, there are no data in elderly nursing home (NH) patients to evaluate gabapentin absorption and elimination. Our objective was to characterize the pharmacokinetics of GBP in elderly nursing home patients maintained on GBP therapy. This was a prospective pharmacokinetic study in elderly nursing home patients (≥60 years) receiving GBP for the management of chronic pain or epilepsy from seven nursing homes. Pharmacokinetic parameters were estimated by nonlinear mixed-effects modeling. A one-compartment model described the data and clearance (CL) was associated with estimated glomerular filtration rate (eGFR) (p < 0.0001). The GBP CL in elderly nursing home patients was 2.93 L/h. After adjusting for the effect of GFR, GBP CL was not affected by age, sex, body weight, or comorbidity scores. No significant effects of body size measures, age, and sex were detected on volume of distribution. Dose-dependent bioavailability of GBP was demonstrated, and the saturable absorption profile was described by a nonlinear hyperbolic function. Prediction-corrected visual predictive check (pc-VPC) suggests adequate fixed- and random-effects models that successfully simulated the mean trend and variability in gabapentin concentration-time profiles. In this analysis, the parameters of the hyperbolic nonlinearity appear to be similar between elderly and younger adults.

KEY WORDS

elderly patients gabapentin nursing home saturable absorption 

Notes

Acknowledgements

This project was supported by the National Institute on Aging of the National Institutes of Health R01AG026390. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

References

  1. 1.
    Lackner TE, Cloyd JC, Thomas LW, Leppik IE. Antiepileptic drug use in nursing home residents: effect of age, gender, and comedication on patterns of use. Epilepsia. 1998;39(10):1083–7.CrossRefPubMedGoogle Scholar
  2. 2.
    Garrard J, Cloyd J, Gross C, et al. Factors associated with antiepileptic drug use among elderly nursing home residents. J Gerontol A Biol Sci Med Sci. 2000;55(7):M384–92.CrossRefPubMedGoogle Scholar
  3. 3.
    Tsai YF, Liu LL, Chung SC. Pain prevalence, experiences, and self-care management strategies among the community-dwelling elderly in Taiwan. J Pain Symptom Manag. 2010;40(4):575–81.CrossRefGoogle Scholar
  4. 4.
    Roy R, Thomas M. A survey of chronic pain in an elderly population. Can Fam Physician. 1986;32:513–6.PubMedPubMedCentralGoogle Scholar
  5. 5.
    Ferrell BA. Pain evaluation and management in the nursing home. Ann Intern Med. 1995;123(9):681–7.CrossRefPubMedGoogle Scholar
  6. 6.
    Helme RD, Gibson SJ. The epidemiology of pain in elderly people. Clin Geriatr Med. 2001;17(3):417–31.CrossRefPubMedGoogle Scholar
  7. 7.
    Elwes RD, Binnie CD. Clinical pharmacokinetics of newer antiepileptic drugs. Lamotrigine, vigabatrin, gabapentin and oxcarbazepine. Clin Pharmacokinet. 1996;30(6):403–15.CrossRefPubMedGoogle Scholar
  8. 8.
    Carlsson KC, van de Schootbrugge M, Eriksen HO, Moberg ER, Karlsson MO, Hoem NO. A population pharmacokinetic model of gabapentin developed in nonparametric adaptive grid and nonlinear mixed effects modeling. Ther Drug Monit. 2009;31(1):86–94.CrossRefPubMedGoogle Scholar
  9. 9.
    Boyd RA, Turck D, Abel RB, Sedman AJ, Bockbrader HN. Effects of age and gender on single-dose pharmacokinetics of gabapentin. Epilepsia. 1999;40(4):474–9.CrossRefPubMedGoogle Scholar
  10. 10.
    Blum RA, Comstock TJ, Sica DA, et al. Pharmacokinetics of gabapentin in subjects with various degrees of renal-function. Clin Pharmacol Ther. 1994;56(2):154–9.CrossRefPubMedGoogle Scholar
  11. 11.
    Lamba M. Pharmacometric analyses of anti-epileptic drugs in special populations (Order No. 3325296). Available from ProQuest Dissertations & Theses A&I: Health & Medicine. (304583377. Retrieved from http://login.ezproxy.lib.umn.edu/login?url=http://search.proquest.com.ezp1.lib.umn.edu/docview/304583377?accountid=14586 2008.
  12. 12.
    Stewart BH, Kugler AR, Thompson PR, Bockbrader HN. A saturable transport mechanism in the intestinal-absorption of gabapentin is the underlying cause of the lack of proportionality between increasing dose and drug levels in plasma. Pharm Res. 1993;10(2):276–81.CrossRefPubMedGoogle Scholar
  13. 13.
    Gidal BE, DeCerce J, Bockbrader HN, et al. Gabapentin bioavailability: effect of dose and frequency of administration in adult patients with epilepsy. Epilepsy Res. 1998;31(2):91–9.CrossRefPubMedGoogle Scholar
  14. 14.
    Yuasa H, Soga N, Kimura Y, Watanabe J. Effect of aging on the intestinal transport of hydrophilic drugs in the rat small intestine. Biol Pharm Bull. 1997;20(11):1188–92.CrossRefPubMedGoogle Scholar
  15. 15.
    Armbrecht HJ, Boltz MA, Kumar VB. Intestinal plasma membrane calcium pump protein and its induction by 1,25(OH)(2)D(3) decrease with age. Am J Physiol. 1999;277(1 Pt 1):G41–7.PubMedGoogle Scholar
  16. 16.
    Toyoshima M, Inada M, Kameyama M. Effects of aging on intracellular transport of vitamin B12 (B12) in rat enterocytes. J Nutr Sci Vitaminol (Tokyo). 1983;29(1):1–10.CrossRefGoogle Scholar
  17. 17.
    Lindeman RD, Tobin J, Shock NW. Longitudinal studies on the rate of decline in renal function with age. J Am Geriatr Soc. 1985;33(4):278–85.CrossRefPubMedGoogle Scholar
  18. 18.
    Rowe JW, Andres R, Tobin JD, Norris AH, Shock NW. The effect of age on creatinine clearance in men: a cross-sectional and longitudinal study. J Gerontol. 1976;31(2):155–63.CrossRefPubMedGoogle Scholar
  19. 19.
    Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis. 1987;40(5):373–83.CrossRefPubMedGoogle Scholar
  20. 20.
    Charlson M, Szatrowski TP, Peterson J, Gold J. Validation of a combined comorbidity index. J Clin Epidemiol. 1994;47(11):1245–51.CrossRefPubMedGoogle Scholar
  21. 21.
    Gill J, Malyuk R, Djurdjev O, Levin A. Use of GFR equations to adjust drug doses in an elderly multi-ethnic group—a cautionary tale. Nephrol Dial Transplant. 2007;22(10):2894–9.CrossRefPubMedGoogle Scholar
  22. 22.
    Stevens LA, Coresh J, Feldman HI, et al. Evaluation of the modification of diet in renal disease study equation in a large diverse population. J Am Soc Nephrol. 2007;18(10):2749–57.CrossRefPubMedGoogle Scholar
  23. 23.
    Lockwood PA, Cook JA, Ewy WE, Mandema JW. The use of clinical trial simulation to support dose selection: application to development of a new treatment for chronic neuropathic pain. Pharm Res. 2003;20(11):1752–9.CrossRefPubMedGoogle Scholar
  24. 24.
    Bergstrand M, Hooker AC, Wallin JE, Karlsson MO. Prediction-corrected visual predictive checks for diagnosing nonlinear mixed-effects models. AAPS J. 2011;13(2):143–51.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Dubois D, Dubois EF. Nutrition metabolism classic—a formula to estimate the approximate surface-area if height and weight be known (reprinted from Archives Internal Medicine, Vol 17, Pg 863, 1916). Nutrition. 1989;5(5):303–11.Google Scholar
  26. 26.
    Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16(1):31–41.CrossRefPubMedGoogle Scholar
  27. 27.
    Armijo JA, Pena MA, Adin J, Vega-Gil N. Association between patient age and gabapentin serum concentration-to-dose ratio—a preliminary multivariate analysis. Ther Drug Monit. 2004;26(6):633–7.CrossRefPubMedGoogle Scholar
  28. 28.
    Gupta A, Li S. Safety and efficacy of once-daily gastroretentive gabapentin in patients with postherpetic neuralgia aged 75 years and over. Drugs Aging. 2013;30(12):999–1008.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    McLean MJ. Clinical pharmacokinetics of gabapentin. Neurology. 1994;44(6 Suppl 5):S17–22. discussion S31-2.PubMedGoogle Scholar
  30. 30.
    Berry DJ, Beran RG, Plunkeft MJ, Clarke LA, Hung WT. The absorption of gabapentin following high dose escalation. Seizure. 2003;12(1):28–36.CrossRefPubMedGoogle Scholar
  31. 31.
    Wilson EA, Sills GJ, Forrest G, Brodie MJ. High dose gabapentin in refractory partial epilepsy: clinical observations in 50 patients. Epilepsy Res. 1998;29(2):161–6.CrossRefPubMedGoogle Scholar
  32. 32.
    Clarkston WK, Pantano MM, Morley JE, Horowitz M, Littlefield JM, Burton FR. Evidence for the anorexia of aging: gastrointestinal transit and hunger in healthy elderly vs. young adults. Am J Physiol. 1997;272(1 Pt 2):R243–8.PubMedGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2017

Authors and Affiliations

  • Ghada F. Ahmed
    • 1
  • Sai Praneeth R. Bathena
    • 1
  • Richard C. Brundage
    • 1
  • Ilo E. Leppik
    • 1
    • 2
    • 3
  • Jeannine M. Conway
    • 1
  • Janice B. Schwartz
    • 4
  • Angela K. Birnbaum
    • 1
    • 2
  1. 1.Department of Experimental and Clinical Pharmacology, College of PharmacyUniversity of MinnesotaMinneapolisUSA
  2. 2.Center for Clinical and Cognitive NeuropharmacologyUniversity of MinnesotaMinneapolisUSA
  3. 3.Department of NeurologyUniversity of MinnesotaMinneapolisUSA
  4. 4.Departments of Medicine and Bioengineering and Therapeutic SciencesUniversity of California, San Francisco and Jewish Home of San FranciscoSan FranciscoUSA

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