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

作者：Larsen Malte Selch; Keizer Ron; Munro Gordon; Mork Arne; Holm Ren; Savic Rada; Kreilgaard Mads^*

来源：Pharmaceutical Research, 2016, 33(5): 1133-1143.

DOI：10.1007/s11095-016-1859-7

• brain
• gabapentin
• pain
• PKPD modelling
• rat

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/ha (TM) 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 mu g/mL, EC (50, brain) = 3.3 mu g/mL).
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.

• 出版日期2016-5