Abstract

Purpose: To fit an absorption-pharmacokinetic model for simulation of Gabapentin in adult and pediatric populations. The model will be able to describe the nonlinear dose dependence of absorption mediated by an amino acid transporter as well as age-dependent renal clearance of Gabapentin.

Methods: GastroPlusTM 5.3 with the PBPKPlus™ Module (Simulations Plus, Inc., Lancaster, CA) was used to simulate adult human plasma concentration time (Cp-time) profiles after oral administration of Gabapentin in adults (doses ranging from 400mg to 1600mg) and children (400mg dose). A physiologically-based pharmacokinetic model (PBPK) was used in all simulations. Tissue/plasma partition coefficients were calculated using in silico physicochemical properties (ADMET Predictor™, Simulations Plus, Lancaster, CA) and the Rodgers (2005, 2007) algorithm. The renal clearance of Gabapentin was estimated to be equal to glomerular filtration rate (GFR) times fraction unbound in plasma (Fup) in both populations. Experimental GFR values from literature were used for both populations. The nonlinear dose dependent absorption of Gabapentin was simulated by incorporating an intestinal influx transporter and in vitro affinity measurements of Gabapentin interaction with LAT1.

10th European Regional ISSX Meeting, May 2008, Vienna, Austria

By Viera Lukacova, Michael B. Bolger, and Walter S. Woltosz