Physiologically based pharmacokinetic (PBPK) modeling of flurbiprofen in different CYP2C9 genotypes

Sang Sup Whang, Chang Keun Cho, Eui Hyun Jung, Pureum Kang, Hye Jung Park, Yun Jeong Lee, Chang Ik Choi, Jung Woo Bae, Hyung Sik Kim, Choon Gon Jang, Seok Yong Lee

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

The aim of this study was to establish the physiologically based pharmacokinetic (PBPK) model of flurbiprofen related to CYP2C9 genetic polymorphism and describe the pharmacokinetics of flurbiprofen in different CYP2C9 genotypes. PK-Sim® software was used for the model development and validation. A total of 16 clinical pharmacokinetic data for flurbiprofen in different CYP2C9 genotypes, dose regimens, and age groups were used for the PBPK modeling. Turnover number (kcat) of CYP2C9 values were optimized to capture the observed profiles in different CYP2C9 genotypes. In the simulation, predicted fraction metabolized by CYP2C9, fraction excreted to urine, bioavailability, and volume of distribution were similar to previously reported values. Predicted plasma concentration-time profiles in different CYP2C9 genotypes were visually similar to the observed profiles. Predicted AUCinf in CYP2C9*1/*2, CYP2C9*1/*3, and CYP2C9*3/*3 genotypes were 1.44-, 2.05-, and 3.67-fold higher than the CYP2C9*1/*1 genotype. The ranges of fold errors for AUCinf, Cmax, and t1/2 were 0.84–1.00, 0.61–1.22, and 0.74–0.94 in development and 0.59–0.98, 0.52–0.97, and 0.61–1.52 in validation, respectively, which were within the acceptance criterion. Thus, the PBPK model was successfully established and described the pharmacokinetics of flurbiprofen in different CYP2C9 genotypes, dose regimens, and age groups. The present model could guide the decision-making of tailored drug administration strategy by predicting the pharmacokinetics of flurbiprofen in various clinical scenarios.

Original languageEnglish
Pages (from-to)584-595
Number of pages12
JournalArchives of Pharmacal Research
Volume45
Issue number8
DOIs
StatePublished - Aug 2022

Keywords

  • CYP2C9
  • Flurbiprofen
  • Genetic polymorphism
  • Pharmacokinetics
  • Physiologically based pharmacokinetic (PBPK) model

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