Journal
ARCHIVES OF PHARMACAL RESEARCH
Volume 45, Issue 5, Pages 352-366Publisher
PHARMACEUTICAL SOC KOREA
DOI: 10.1007/s12272-022-01388-0
Keywords
Physiologically based pharmacokinetic (PBPK) model; Piroxicam; Genetic polymorphism; Pharmacokinetics
Categories
Funding
- Basic Science Research Program through the National Research Foundation of Korea (NRF) - Ministry of Science, ICT, and Future Planning [NRF-2019R1A2C1004582]
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This study developed a physiologically based pharmacokinetic (PBPK) model for piroxicam and validated its relationship with CYP2C9 genetic polymorphism. The model accurately captured the pharmacokinetic alterations of piroxicam according to CYP2C9 genetic polymorphism.
Piroxicam is a non-steroidal anti-inflammatory drug used to alleviate symptoms of osteoarthritis and rheumatoid arthritis. CYP2C9 genetic polymorphism significantly influences the pharmacokinetics of piroxicam. The objective of this study was to develop and validate the piroxicam physiologically based pharmacokinetic (PBPK) model related to CYP2C9 genetic polymorphism. PK-Sim (R) version 10.0 was used for the PBPK modeling. The PBPK model was evaluated by predicted and observed plasma concentration-time profiles, fold errors of predicted to observed pharmacokinetic parameters, and a goodness-of-fit plot. The turnover number (k(cat)) of CYP2C9 was adjusted to capture the pharmacokinetics of piroxicam in different CYP2C9 genotypes. The population PBPK model overall accurately described and predicted the plasma concentration-time profiles in different CYP2C9 genotypes. In our simulations, predicted AUC(inf) in CYP2C9*1/*2, CYP2C9*1/*3, and CYP2C9*3/*3 genotypes were 1.83-, 2.07-, and 6.43-fold higher than CYP2C9*1/*1 genotype, respectively. All fold error values for AUC, C-max, and t(1/2) were included in the acceptance criterion with the ranges of 0.57-1.59, 0.63-1.39, and 0.65-1.51, respectively. The range of fold error values for predicted versus observed plasma concentrations was 0.11-3.13. 93.9% of fold error values were within the two-fold range. Average fold error, absolute average fold error, and root mean square error were 0.93, 1.27, and 0.72, respectively. Our model accurately captured the pharmacokinetic alterations of piroxicam according to CYP2C9 genetic polymorphism.
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