TY - JOUR
T1 - Physiologically based pharmacokinetic (PBPK) modeling of piroxicam with regard to CYP2C9 genetic polymorphism
AU - Cho, Chang Keun
AU - Kang, Pureum
AU - Park, Hye Jung
AU - Ko, Eunvin
AU - Mu, Chou Yen
AU - Lee, Yun Jeong
AU - Choi, Chang Ik
AU - Kim, Hyung Sik
AU - Jang, Choon Gon
AU - Bae, Jung Woo
AU - Lee, Seok Yong
N1 - Publisher Copyright:
© 2022, The Pharmaceutical Society of Korea.
PY - 2022/5
Y1 - 2022/5
N2 - 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® 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 (kcat) 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 AUCinf 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, Cmax, and t1/2 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.
AB - 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® 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 (kcat) 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 AUCinf 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, Cmax, and t1/2 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.
KW - CYP2C9
KW - Genetic polymorphism
KW - Pharmacokinetics
KW - Physiologically based pharmacokinetic (PBPK) model
KW - Piroxicam
UR - http://www.scopus.com/inward/record.url?scp=85131060527&partnerID=8YFLogxK
U2 - 10.1007/s12272-022-01388-0
DO - 10.1007/s12272-022-01388-0
M3 - Article
C2 - 35639246
AN - SCOPUS:85131060527
SN - 0253-6269
VL - 45
SP - 352
EP - 366
JO - Archives of Pharmacal Research
JF - Archives of Pharmacal Research
IS - 5
ER -