title: Pharmacokinetic/Pharmacodynamic Relationship of Gabapentin in a CFA-induced Inflammatory Hyperalgesia Rat Model.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100, Copenhagen, Denmark.
authors.forename: Malte Selch
authors.initials: MS
authors.lastname: Larsen
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, University of California, 1700 4th Street,, San Francisco, California, 94580, USA.
authors.forename: Ron
authors.initials: R
authors.lastname: Keizer
authors.affiliation: Neurodegeneration In Vivo, H. Lundbeck A/S, Ottiliavej 9, 2500, Valby, Denmark.
authors.forename: Gordon
authors.initials: G
authors.lastname: Munro
authors.affiliation: Synaptic Transmission In Vivo, H. Lundbeck A/S, Ottiliavej 9, 2500, Valby, Denmark.
authors.forename: Arne
authors.initials: A
authors.lastname: Mørk
authors.affiliation: Pharmaceutical Science and CMC Biologics, H. Lundbeck A/S, Ottiliavej 9, 2500, Valby, Denmark.
authors.forename: René
authors.initials: R
authors.lastname: Holm
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, University of California, 1700 4th Street,, San Francisco, California, 94580, USA.
authors.forename: Rada
authors.initials: R
authors.lastname: Savic
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100, Copenhagen, Denmark. mdkd@novonordisk.com.|Novo Nordisk A/S, Novo Nordisk Park City, 2760, Maaloev, Denmark. mdkd@novonordisk.com.
authors.forename: Mads
authors.initials: M
authors.lastname: Kreilgaard
mesh_terms: D000588:Amines / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology* / Q000627:therapeutic use; D000700:Analgesics / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D001682:Biological Availability; D001921:Brain / Q000378:metabolism; D003198:Computer Simulation; D003509:Cyclohexanecarboxylic Acids / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology* / Q000627:therapeutic use; D000077206:Gabapentin; D006930:Hyperalgesia / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D008954:Models, Biological; D051381:Rats; D017207:Rats, Sprague-Dawley; D005680:gamma-Aminobutyric Acid / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000588:Amines; D000700:Analgesics; D003509:Cyclohexanecarboxylic Acids; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin
keywords: PKPD modelling; brain; gabapentin; pain; rat