Prediction of Flurbiprofen Pharmacokinetics by CYP2C9 Genotypes in Populations Utilizing a Physiological Based Pharmacokinetic Modeling

Abstract

This study focuses on the prediction of Flurbiprofen metabolism in vivo by CYP2C9 genotypes. C‐max‐, AUC, Tmax‐, half‐life (T1/2) and Clearance (CL/F) are primary parameters in physiologically based pharmacokinetic (PBPK) modeling. Flurbiprofen of non‐steroidal anti‐inflammation drugs (NSAIDs) is used to treat inflammation in patients with arthritis. The major metabolic pathway of flurbiprofen metabolized to 4′‐hydroxyflurbiprofen is mediated by cytochrome P450 2C9 (CYP2C9) enzyme. Therefore, CYP2C9 enzyme activity primarily influences on flurbiprofen concentrations. So CYP2C9 enzyme isoform is considered as a clinical parameter of flurbiprofen. 16 healthy Koran subjects with CYP2C9 *1/*1 (n=10) and CYP2C9 *1/*3 (n=6) genotypes were recruited in the present pharmacokinetic study of flurbiprofen. All subjects received 40mg single oral dose of flurbiprofen. Blood samples were collected up before and after the administration of flurbiprofen. In this study, PK‐Sim® (PK‐Sim ® 7.4, Bayer AG, Wuppertal, Germany) was used to predict pharmacokinetics of CYP2C9 enzyme isoform. To verify the simulation, pharmacokinetic parameters were compared to monographic in vivo data and our flurbiprofen clinic research data. For assessment of Flurbiprofen PBPK model, an acceptable criterion based on observed human pharmacokinetic data is calculated using recently published methods. In our clinical research, AUC0–24, AUCinf, Cmax, Tmax, half‐life (T1/2), and clearance (CL/F) was dramatically changed in CYP2C9*1/*3 compared to CYP2C9*1/*1 genotype. The CYP2C9*3 allele can affect the pharmacokinetics of flurbiprofen. For metabolism, input parameters of specific Vmax in an in vitro assay using recombinant enzyme for CYP2C9*1 and CYP2C9*3 were 13.79 and 11.35 pmol/min/pmol, respectively. And, input parameters of Km for CYP2C9*1 and CYP2C9*3 were 8.76 and 16.0 μM, respectively. PK data were calculated in modeling and met the model acceptance criterion (99.998% confidence interval). Base on the results of our clinical data, A PBPK model of flurbiprofen was successfully developed using the Middle‐out method. These models developed in the CYP2C9*1/*1 and scaled to those with reduced enzyme activity. The presented PBPK model shows the pharmacokinetics after a single dose of flurbiprofen with the CYP2C9 genotype. The obtained pharmacokinetic parameters by the simulation were validated by comparing the data from the literature. Our PBPK model of flurbiprofen can contribute to the determination of the optimal flurbiprofen dosage considering inter‐individual genetic differences. Also, this PBPK model can be useful for personalized medicine for special patient groups. Pharmacokinetics of flurbiprofen in CYP2C9*1/*1 (EM) and CYP2C9*1/*3 (IM) genotype groups. (Each group was compared using by one‐way ANOVA) Parameter CYP2C9 EM (n=10) CYP2C9 IM (n=6) P value Cmax (ug/mL) 6.4 ± 1.3 6.8 ± 1.8 N.S. Tmax (hr) 1.6 ± 1.0 1.8 ± 0.9 N.S. T1/2 (hr) 5.1 ± 0.3 6.1 ± 0.6 0.0004 CL/F (L/hr) 1.6 ± 0.2 1.1 ± 0.1 <0.0001 AUC0–24 (ug·hr/mL) 25.2 ± 2.6 34.5 ± 2.2 <0.0001 AUCinf (ug·hr/mL) 26.0 ± 2.7 36.6 ± 2.2 <0.0001 Validation of flurbiprofen PBPK modeling in relation to CYP2C9 population data. Dose Parameter Mean Observed Mean Simulated 2‐fold error (0.5<Si/Ob<2) 150 mg Oelkers 1997 Cmax [ug/mL] 18.07 19.45 0.93 AUCinf [ug·h/mL] 137.65 120.46 1.14 AUCend [ug·h/mL] No data 116.18 ‐ Tmax [hr] 1.5 1.10 0.73 T1/2 [hr] 5.9 5.71 0.97 100 mg Walter 1992 (In younger patients) Cmax [ug/mL] 11.7 11.07 1.06 AUCinf [ug·h/mL] 58.3 48.52 1.20 AUCend [ug·h/mL] 49.0 45.08 1.09 Tmax [hr] 2.3 1.05 0.46 T1/2 [hr] 6.2 4.36 0.70 100 mg Walter 1992 (In elderly patients) Cmax [ug/mL] 12.7 15.0 0.85 AUCinf [ug·h/mL] 69.6 83.9 0.83 AUCend [ug·h/mL] 56.8 74.6 0.76 Tmax [hr] 1.7 1.05 0.62 T1/2 [hr] 5.6 3.92 0.7 150 mg Yan‐Mei 2009 Cmax [ug/mL] 21.24 20.45 1.04 AUCinf [ug·h/mL] 129.82 112.41 1.15 AUCend [ug·h/mL] 121.99 110.26 1.11 Tmax [hr] 2.18 1.15 0.56 T1/2 [hr] 4.42 4.76 1.08 100 mg Laurie 2012 Cmax [ug/mL] 12.3 1062 1.15 AUCinf [ug·h/mL] 75.4 49.49 1.52 AUCend [ug·h/mL] No data 49.21 ‐ Tmax [hr] 2.6 1.05 0.40 T1/2 [hr] 42 3.60 0.86