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

Author(s)

Silva, Carolina de Miranda ^{[1, 2, 3]} ; Rocha, Adriana ^[1] ; Tozatto, Eduardo ^[1] ; da Silva, Lucienir Maria ^[4] ; Donadi, Eduardo Antnio ^[4] ; Dalla Costa, Teresa ^[3] ; Lanchote, Vera Lucia ^[1] ; Schmidt, Stephan ^[2] ; Bulitta, Jurgen B. ^[2]

Affiliation

^[1] Univ Sao Paulo, Fac Ciencias Farmaceut Ribeirao Preto, Dept Anal Clin Toxicol & Bromatol, Ribeirao Preto, SP - Brazil

^[2] Univ Florida, Dept Pharmaceut, Coll Pharm, Ctr Pharmacometr & Syst Pharmacol, 6550 Sanger Rd, Orlando, FL 32827 - USA

^[3] Univ Fed Rio Grande do Sul, Dept Prod & Controle Med, Fac Farm, Porto Alegre, RS - Brazil

^[4] Univ Sao Paulo, Dept Clin Med, Fac Med Ribeirao Preto, Ribeirao Preto, SP - Brazil

• Document type: Journal article
• Source: AAPS JOURNAL; v. 19, n. 6, p. 1814-1825, NOV 2017.
• Web of Science Citations: 1

Abstract

Cyclooxygenase-2 (COX-2) isoform has a critical role in the development of pain. Inhibition of COX-2 in vitro serves as a biomarker for nonsteroidal anti-inflammatory drugs (NSAIDs). The NSAID concentrations yielding 80% COX-2 inhibition (IC80) correlate with therapeutic doses to achieve analgesia across multiple COX-2 inhibitors. However, there are no time-course models relating COX-2 inhibition with decreased pain. 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 reported in 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- and S-etodolac were determined by LC-MS/MS and simultaneously modeled. Literature in vitro IC50 data for COX-2 inhibition by S-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 for R-etodolac and 26.8 L/h for S-etodolac. Volume of distribution at steady-state was 14.6 L for R-etodolac and 45.8 L for S-etodolac. Inhibition of COX-2 by 78.1% caused a half-maximal pain decrease. The time-course of pain decrease following ibuprofen was successfully predicted via 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. (AU)

• FAPESP's process: 10/12922-1 - POPULATION PK-PD (PHARMACOKINETIC-PHARMACODYNAMIC) OF ETODOLAC IN HEALTHY VOLUNTEERS TREATED WITH RACEMIC DRUG AND ITS PURE EUTOMER.
• Grantee: Carolina de Miranda Silva
• Support Opportunities: Scholarships in Brazil - Post-Doctoral