TY - JOUR
T1 - Physiologically based pharmacokinetic (PBPK) modeling of flurbiprofen in different CYP2C9 genotypes
AU - Whang, Sang Sup
AU - Cho, Chang Keun
AU - Jung, Eui Hyun
AU - Kang, Pureum
AU - Park, Hye Jung
AU - Lee, Yun Jeong
AU - Choi, Chang Ik
AU - Bae, Jung Woo
AU - Kim, Hyung Sik
AU - Jang, Choon Gon
AU - Lee, Seok Yong
N1 - Publisher Copyright:
© 2022, The Pharmaceutical Society of Korea.
PY - 2022/8
Y1 - 2022/8
N2 - 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.
AB - 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.
KW - CYP2C9
KW - Flurbiprofen
KW - Genetic polymorphism
KW - Pharmacokinetics
KW - Physiologically based pharmacokinetic (PBPK) model
UR - http://www.scopus.com/inward/record.url?scp=85137070200&partnerID=8YFLogxK
U2 - 10.1007/s12272-022-01403-4
DO - 10.1007/s12272-022-01403-4
M3 - Article
AN - SCOPUS:85137070200
SN - 0253-6269
VL - 45
SP - 584
EP - 595
JO - Archives of Pharmacal Research
JF - Archives of Pharmacal Research
IS - 8
ER -