POPULATION PK-PD (PHARMACOKINETIC-PHARMACODYNAMIC) OF ETODOLAC IN HEALTHY VOLUNTEERS TREATED WITH RACEMIC DRUG AND ITS PURE EUTOMER.

Abstract

Etodolac is a chiral non-steroidal antiinflammatory drug which inhibits cyclooxigenase-2(COX-2). It is clinically available as a racemic mixture of its two enantiomers: (S)-(+)-etodolac (S-ETO)and (R)-(-)-etodolac (R-ETO). The present study aims to evaluate the population pharmacokinetic-pharmacodynamic relantionship (PK-PD) of etodolac in healthy volunteers treated with racemic drug and its pure eutomer S-ETO. A crossover randomized study will be conducted in 4 phases on 8 healthy volunteers treated with a single oral dose of racemic etodolac 400 mg, racemic etodolac 600mg, pure S-ETO 200mg and pure S-ETO 300mg, with a wash-out period of 1 week. Blood and urine samples will be collected up to 36 hours after drug administration. Plasma (bound and free drug) and urinary concentrations of etodolac enantiomers and its glucuronide metabolites will be quantified through LC-MS/MS coupled to chiral column. COX-2 activity will be evaluated through analysis of PGE2 plasma levels subsequent to ex vivo induction by lipopolysaccaride. Population PK-PD relationship between pharmacokinetic parameters of S-ETO and inhibition of COX-2 activity will be built with the aim of NONMEM software. Differences between pharmacokinetic and pharmacodynamic parameters observed for S-ETO after treatment with racemic and enantiomeric pure drug will be evaluated through Mann-Whitney test, with significance levels fixed at p<0,05.