Skip to main content

Advertisement

SpringerLink
Log in

Pharmacokinetic/Pharmacodynamic Relationship of Gabapentin in a CFA-induced Inflammatory Hyperalgesia Rat Model

  • Research Paper
  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

ABSTRACT

Purpose

Gabapentin displays non-linear drug disposition, which complicates dosing for optimal therapeutic effect. Thus, the current study was performed to elucidate the pharmacokinetic/pharmacodynamic (PKPD) relationship of gabapentin’s effect on mechanical hypersensitivity in a rat model of CFA-induced inflammatory hyperalgesia.

Methods

A semi-mechanistic population-based PKPD model was developed using nonlinear mixed-effects modelling, based on gabapentin plasma and brain extracellular fluid (ECF) time-concentration data and measurements of CFA-evoked mechanical hyperalgesia following administration of a range of gabapentin doses (oral and intravenous).

Results

The plasma/brain ECF concentration-time profiles of gabapentin were adequately described with a two-compartment plasma model with saturable intestinal absorption rate (K m  = 44.1 mg/kg, V max  = 41.9 mg/h∙kg) and dose-dependent oral bioavailability linked to brain ECF concentration through a transit compartment. Brain ECF concentration was directly linked to a sigmoid E max function describing reversal of hyperalgesia (EC 50, plasma  = 16.7 μg/mL, EC 50, brain  = 3.3 μg/mL).

Conclusions

The proposed semi-mechanistic population-based PKPD model provides further knowledge into the understanding of gabapentin’s non-linear pharmacokinetics and the link between plasma/brain disposition and anti-hyperalgesic effects. The model suggests that intestinal absorption is the primary source of non-linearity and that the investigated rat model provides reasonable predictions of clinically effective plasma concentrations for gabapentin.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

Abbreviations

BBB:

Blood–brain barrier

CFA:

Complete Freund’s adjuvant

CWRES:

Conditional weighted residuals

ECF:

Extracellular fluid

FIP:

Formalin induced pain

PKPD:

Pharmacokinetic/Pharmacodynamic

VPC:

Visual predictive check

REFERENCES

  1. Yawn BP, Wollan PC, Weingarten TN, Watson JC, Hooten WM, Melton Iii LJ. The prevalence of neuropathic pain: clinical evaluation compared with screening tools in a community population. Pain Med. 2009;10(3):586–93.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Kukkar A, Bali A, Singh N, Jaggi AS. Implications and mechanism of action of gabapentin in neuropathic pain. Arch Pharm Res. 2013;36(3):237–51.

    Article  CAS  PubMed  Google Scholar 

  3. Woolf CJ, Salter MW. Neuronal plasticity: increasing the gain in pain. Science. 2000;288(5472):1765–9.

    Article  CAS  PubMed  Google Scholar 

  4. Boulton AJM. Treatment of symptomatic diabetic neuropathy. Diabetes Metab Res Rev. 2003;19(S1):16–21.

    Article  Google Scholar 

  5. Moore RA, Wiffen PJ, Derry S, McQuay HJ. Gabapentin for chronic neuropathic pain and fibromyalgia in adults. Cochrane Database Syst Rev. 2011;3:1–91.

    Google Scholar 

  6. Gidal BE, DeCerce J, Bockbrader HN, Gonzalez J, Kruger S, Pitterle ME, et al. Gabapentin bioavailability: effect of dose and frequency of administration in adult patients with epilepsy. Epilepsy Res. 1998;31(2):91–9.

    Article  CAS  PubMed  Google Scholar 

  7. Larsen M, Frølund S, Nøhr M, Nielsen C, Garmer M, Kreilgaard M, et al. In vivo and In vitro evaluations of intestinal gabapentin absorption: effect of dose and inhibitors on carrier-mediated transport. Pharm Res. 2014:1–12.

  8. Luer MS, Hamani C, Dujovny M, Gidal B, Cwik M, Deyo K, et al. Saturable transport of gabapentin at the blood-brain barrier. Neurol Res. 1999;21(6):559–62.

    CAS  PubMed  Google Scholar 

  9. Urban TJ, Brown C, Castro RA, Shah N, Mercer R, Huang Y, et al. Effects of genetic variation in the novel organic cation transporter, OCTN1, on the renal clearance of gabapentin. Clin Pharmacol Ther. 2008;83(3):416–21.

    Article  CAS  PubMed  Google Scholar 

  10. Hurley RW, Chatterjea D, Rose Feng M, Taylor CP, Hammond DL. Gabapentin and pregabalin Can interact synergistically with naproxen to produce antihyperalgesia. Anesthesiology. 2002;97(5):1263–73.

    Article  CAS  PubMed  Google Scholar 

  11. Iyengar S, Webster AA, Hemrick-Luecke SK, Xu JY, Simmons RMA. Efficacy of duloxetine, a potent and balanced serotonin-norepinephrine reuptake inhibitor in persistent pain models in rats. J Pharmacol Exp Ther. 2004;311(2):576–84.

    Article  CAS  PubMed  Google Scholar 

  12. Todorovic SM, Rastogi AJ, Jevtovic-Todorovic V. Potent analgesic effects of anticonvulsants on peripheral thermal nociception in rats. Br J Pharmacol. 2003;140(2):255–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Taneja A, Troconiz IF, Danhof M, Della PO. Semi-mechanistic modelling of the analgesic effect of gabapentin in the formalin-induced rat model of experimental pain. Pharm Res. 2014;31(3):593–606.

    Article  CAS  PubMed  Google Scholar 

  14. Taneja A, Nyberg J, de Lange ECM, Danhof M, Della PO. Application of ED-optimality to screening experiments for analgesic compounds in an experimental model of neuropathic pain. J Pharmacokinet Pharmacodyn. 2012;39(6):673–81.

    Article  CAS  PubMed  Google Scholar 

  15. Lockwood P, Cook J, Ewy W, Mandema J. 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.

    Article  CAS  PubMed  Google Scholar 

  16. Swanson LW. The rat brain in stereotaxic coordinates. In: Paxinos G, Watson C, editors. Academic Press, San Diego (1982), vii + 153, ISBN: 0 125 47620 5. Trends Neurosci. 1984;7(2):53.

  17. Munro G, Erichsen HK, Rae MG, Mirza NR. A question of balance – Positive versus negative allosteric modulation of GABAA receptor subtypes as a driver of analgesic efficacy in rat models of inflammatory and neuropathic pain. Neuropharmacology. 2011;61(1–2):121–32.

    Article  CAS  PubMed  Google Scholar 

  18. Bauer RJ. NONMEM users guide. Ellicott City: ICON Development Solutions; 2011.

    Google Scholar 

  19. Keizer RJ, Karlsson MO, Hooker A. Modeling and simulation workbench for NONMEM: tutorial on Pirana, PsN, and Xpose. CPT Pharmacometrics Syst Pharmacol. 2013;2, e50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Development Core Team R. R: A language and environment for statistical computing. Vienna: R Foundation for Statistical Computing; 2013.

    Google Scholar 

  21. Jonsson EN, Karlsson MO. Xpose—an S-PLUS based population pharmacokinetic/pharmacodynamic model building aid for NONMEM. Comput Methods Prog Biomed;58(1):51–64.

  22. Wickham H. ggplot2: elegant graphics for data analysis. New York: Springer; 2009.

    Book  Google Scholar 

  23. Wang Y, Welty D. The simultaneous estimation of the influx and efflux blood-brain barrier permeabilities of gabapentin using a microdialysis-pharmacokinetic approach. Pharm Res. 1996;13(3):398–403.

    Article  CAS  PubMed  Google Scholar 

  24. Gur E, Waner T. The variability of organ weight background data in rats. Lab Anim. 1993;27(1):65–72.

    Article  CAS  PubMed  Google Scholar 

  25. Radulovic LL, Türck D, von Hodenberg A, Vollmer KO, McNally WP, DeHart PD, et al. Disposition of gabapentin (neurontin) in mice, rats, dogs, and monkeys. Drug Metab Dispos. 1995;23(4):441–8.

    CAS  PubMed  Google Scholar 

  26. Upton RN, Mould DR. Basic concepts in population modeling, simulation, and model-based drug development: part 3 - introduction to pharmacodynamic modeling methods. CPT Pharmacometrics Syst Pharmacol. 2014;3, e88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Dumas E, Pollack G. Opioid tolerance development: a pharmacokinetic/pharmacodynamic perspective. AAPS J. 2008;10(4):537–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. 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.

    Article  CAS  PubMed  Google Scholar 

  30. Welty DF, Schielke GP, Vartanian MG, Taylor CP. Gabapentin anticonvulsant action in rats: disequilibrium with peak drug concentrations in plasma and brain microdialysate. Epilepsy Res. 1993;16(3):175–81.

    Article  CAS  PubMed  Google Scholar 

  31. Vollmer KO, von Hodenberg A, Kölle EU. Pharmacokinetics and metabolism of gabapentin in rat, dog and man. Arzneimittelforschung. 1986;36(5):830–9.

    CAS  PubMed  Google Scholar 

  32. Cundy KC, Annamalai T, Bu L, De Vera J, Estrela J, Luo W, et al. XP13512 [(±)-1-([(α-Isobutanoyloxyethoxy)carbonyl] aminomethyl)-1-cyclohexane acetic acid], a novel gabapentin prodrug: II. Improved oral bioavailability, dose proportionality, and colonic absorption compared with gabapentin in rats and monkeys. J Pharmacol Exp Ther. 2004;311(1):324–33.

    Article  CAS  PubMed  Google Scholar 

  33. Yang RH, Xing JL, Duan JH, Hu SJ. Effects of gabapentin on spontaneous discharges and subthreshold membrane potential oscillation of type a neurons in injured DRG. Pain. 2005;116(3):187–93.

    Article  CAS  PubMed  Google Scholar 

  34. Chen SR, Xu Z, Pan HL. Stereospecific effect of pregabalin on ectopic afferent discharges and neuropathic pain induced by sciatic nerve ligation in rats. Anesthesiology. 2001;95(6):1473–9.

    Article  CAS  PubMed  Google Scholar 

  35. Pan HL, Eisenach JC, Chen SR. Gabapentin suppresses ectopic nerve discharges and reverses allodynia in neuropathic rats. J Pharmacol Exp Ther. 1999;288(3):1026–30.

    CAS  PubMed  Google Scholar 

  36. Yang J-L, Xu B, Li S-S, Zhang W-S, Xu H, Deng X-M, et al. Gabapentin reduces CX3CL1 signaling and blocks spinal microglial activation in monoarthritic rats. Mol Brain. 2012;5(1):1–12.

    Article  CAS  Google Scholar 

  37. Luo ZD, Chaplan SR, Higuera ES, Sorkin LS, Stauderman KA, Williams ME, et al. Upregulation of dorsal root ganglion α2δ calcium channel subunit and its correlation with allodynia in spinal nerve-injured rats. J Neurosci. 2001;21(6):1868–75.

    CAS  PubMed  Google Scholar 

  38. Porchet HC, Benowitz NL, Sheiner LB. Pharmacodynamic model of tolerance: application to nicotine. J Pharmacol Exp Ther. 1988;244(1):231–6.

    CAS  PubMed  Google Scholar 

  39. Yi H, Kim MA, Back SK, Eun JS, Na HS. A novel rat forelimb model of neuropathic pain produced by partial injury of the median and ulnar nerves. Eur J Pain. 2011;15(5):459–66.

    Article  PubMed  Google Scholar 

  40. Whiteside GT, Adedoyin A, Leventhal L. Predictive validity of animal pain models? A comparison of the pharmacokinetic–pharmacodynamic relationship for pain drugs in rats and humans. Neuropharmacology. 2008;54(5):767–75.

    Article  CAS  PubMed  Google Scholar 

Download references

ACKNOWLEDGMENTS AND DISCLOSURES

The personnel at the animal facilities at H. Lundbeck A/S are acknowledged and appreciated for their skilful and flexible handling of the animal study.

Author information

Authors and Affiliations

  1. Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100, Copenhagen, Denmark

    Malte Selch Larsen & Mads Kreilgaard

  2. Department of Bioengineering and Therapeutic Sciences, University of California, 1700 4th Street,, San Francisco, California, 94580, USA

    Ron Keizer & Rada Savic

  3. Neurodegeneration In Vivo, H. Lundbeck A/S, Ottiliavej 9, 2500, Valby, Denmark

    Gordon Munro

  4. Synaptic Transmission In Vivo, H. Lundbeck A/S, Ottiliavej 9, 2500, Valby, Denmark

    Arne Mørk

  5. Pharmaceutical Science and CMC Biologics, H. Lundbeck A/S, Ottiliavej 9, 2500, Valby, Denmark

    René Holm

  6. Novo Nordisk A/S, Novo Nordisk Park City, 2760, Maaloev, Denmark

    Mads Kreilgaard

Authors
  1. Malte Selch Larsen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ron Keizer
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Gordon Munro
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Arne Mørk
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. René Holm
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Rada Savic
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Mads Kreilgaard
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mads Kreilgaard.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Larsen, M.S., Keizer, R., Munro, G. et al. Pharmacokinetic/Pharmacodynamic Relationship of Gabapentin in a CFA-induced Inflammatory Hyperalgesia Rat Model. Pharm Res 33, 1133–1143 (2016). https://doi.org/10.1007/s11095-016-1859-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11095-016-1859-7

KEY WORDS

Search

Navigation