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

Pharmaceutical Research
Malte Selch LarsenMads Kreilgaard

Abstract

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. 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). 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). The proposed semi-mechanistic population-based PKPD model provides further knowledge into the understanding of gabapen...Continue Reading

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Citations

Jul 6, 2016·Pharmaceutical Research·Theodoros PapathanasiouTrine Meldgaard Lund
Oct 12, 2018·Journal of Veterinary Internal Medicine·Derek AdrianB Duncan X Lascelles
May 20, 2018·Journal of Pharmacokinetics and Pharmacodynamics·Wilhelmus E A de WitteElizabeth C M de Lange
Jun 2, 2021·Journal of Veterinary Internal Medicine·Jennifer E Slovak, Ana P Costa
Sep 10, 2017·The Veterinary Journal·Derek AdrianB Duncan X Lascelles

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