Physiologically Based Pharmacokinetic (PBPK) Modeling and Simulation of Lornoxicam to Develop Personalized Drug Optimization regarding to CYP2C9 Genetic Polymorphism

Abstract

Lornoxicam is a non‐steroidal anti‐inflammatory drug (NSAID) of oxicam class that has analgesic and anti‐inflammatory effects. Lornoxicam decreases various prostaglandin synthesis via inhibition of cyclo‐oxygenase (COX). Lornoxicam is primarily metabolized to 5’‐hydroxy lornoxicam through cytochrome P450 2C9 (CYP2C9) enzyme. Polymorphism of the CYP2C9 enzyme, e.g., CYP2C9*3 and CYP2C9*13, are associated with decreased activity of CYP2C9. Consequently, the difference of CYP2C9 activity by polymorphism triggers diverse drug concentration and response despite equal dose administration. For individual drug optimization, we develop a predictable pharmacokinetic model based on physiological characteristics related to CYP2C9 activity. In our research, 13 healthy Korean male subjects were included in the pharmacokinetic study of lornoxicam. All subjects were divided into three different CYP2C9*1/*1, CYP2C9*1/*3, and CYP2C9*1/*13 groups. 8mg dose of lornoxicam was administered to individual subjects. After administration, venous blood samples were collected and analyzed by HPLC‐UV method. Pharmacokinetic parameter values were predicted using PBPK software, PK‐Sim® 8. Vmax and Km parameter values were adjusted to reflect a difference in CYP2C9 activity based on in vitro CYP2C9 kinetic studies of lornoxicam. Simulated pharmacokinetic data were compared to our clinical data for the development and verification of the lornoxicam model and assessed for validity using a 99.998% confidence interval and two‐fold error criteria. In our clinical trial, pharmacokinetic parameters, e.g., AUCinf, Cmax, Tmax, and half‐life, were considerably changed in CYP2C9*1/*3 and CYP2C9*1/*13 groups compared to CYP2C9*1/*1 group. Firstly, AUCinf, Cmax, Tmax, and half‐life values are 2730.2, 655.7, 2.2, 2.74 in CYP2C9*1/*1 group, secondly 5464, 815.3, 1.6, 4.99 in CYP2C9*1/*3, finally 5315, 935.1, 2.3, 5.19 in CYP2C9*1/*13 respectively. For predicted data for this is as follows: 3099.2, 640.9, 1.5, 2.9 in CYP2C9*1/*1, 5312.5, 748.3, 1.6, 5.2 in CYP2C9*1/*3, 5551, 782.7, 1.6, 4.17 in CYP2C9*1/*13. Based on these result, simulated values were within suitable assessment for model development. Values for verification conducted simulation in Chinese ethnic also were fit in the assessment. Therefore, the PBPK model of lornoxicam was confirmed development successfully. Unfortunately, we could not find pharmacokinetic profiles in the ethnic group except the Chinese. So, we verified the PBPK model by conducting simulation only in Chinese ethnic. Because of this limitation, we expect to be able to develop a more validated model through the verification of various ethnic in further studies. PBPK model of lornoxicam in CYP2C9*1/*1 genotypes. PBPK model of lornoxicam in CYP2C9*1/*3 genotypes. Km and Vmax values were scaled