Malte Selch Larsen1, Ron Keizer2, Gordon Munro3, Arne Mørk4, René Holm5, Rada Savic2, Mads Kreilgaard6,7. 1. Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100, Copenhagen, Denmark. 2. Department of Bioengineering and Therapeutic Sciences, University of California, 1700 4th Street,, San Francisco, California, 94580, USA. 3. Neurodegeneration In Vivo, H. Lundbeck A/S, Ottiliavej 9, 2500, Valby, Denmark. 4. Synaptic Transmission In Vivo, H. Lundbeck A/S, Ottiliavej 9, 2500, Valby, Denmark. 5. Pharmaceutical Science and CMC Biologics, H. Lundbeck A/S, Ottiliavej 9, 2500, Valby, Denmark. 6. Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100, Copenhagen, Denmark. mdkd@novonordisk.com. 7. Novo Nordisk A/S, Novo Nordisk Park City, 2760, Maaloev, Denmark. mdkd@novonordisk.com.
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.
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.
Entities:
Keywords:
PKPD modelling; brain; gabapentin; pain; rat
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