Development of an Enantioselective and Biomarker-Informed Translational Population Pharmacokinetic/Pharmacodynamic Model for Etodolac

This study aimed to characterize the relationship between NSAID concentrations,in vitro COX-2 inhibition, and acute pain decrease in humans over time by a translational approach using clinical pharmacokinetic and literature reportedin vitro and clinical pharmacodynamic data. In a two-way cross-over study, eight healthy volunteers received 300 and 400  mg racemic etodolac, a preferential COX-2 inhibitor.R- andS-etodolac were determined by LC-MS/MS and simultaneously modeled. Literaturein vitro IC50 data for COX-2 inhibition byS-etodolac were used to fit adjusted pain score profiles from dental patients receiving etodolac. External model qualification was performed using published ibuprofen data. Etodolac absorption was highly variable due to gastric transit kinetics and low aqueous solubility. The disposition parameters differed substantially between enantiomers with a total clearance of 2.21  L/h forR-etodolac and 26.8  L/h forS-etodolac. Volume of distribution at steady-state was 14.6  L forR-etodolac and 45.8  L forS-etodolac. Inhibition of COX-2 by 78.1% caused a half-maximal pain decrease. The time-course of pain decrease following ibuprofen was successfully predictedvia the developed translational model. This proposed enantioselective pharmacodynamic-informed approach presents the first quantitative time-course model for COX-2 induced pain inhibition in patients.
Source: The AAPS Journal - Category: Drugs & Pharmacology Source Type: research