Physiologically based pharmacokinetic (PBPK) modeling to predict the pharmacokinetics of irbesartan in different CYP2C9 genotypes

Chang-Keun Cho,Pureum Kang,Choon-Gon Jang,Seok-Yong Lee,YunJeong Lee,Chang-Ik Choi 대한약학회 2023 Archives of Pharmacal Research Vol.46 No.12

Irbesartan, a potent and selective angiotensin II type-1 (AT1) receptor blocker (ARB), is one of the representative medications for the treatment of hypertension. Cytochrome P450 (CYP) 2C9 is primarily involved in the oxidation of irbesartan. CYP2C9 is highly polymorphic, and genetic polymorphism of this enzyme is the leading cause of significant alterations in the pharmacokinetics of irbesartan. This study aimed to establish the physiologically based pharmacokinetic (PBPK) model to predict the pharmacokinetics of irbesartan in different CYP2C9 genotypes. The irbesartan PBPK model was established using the PK-Sim® software. Our previously reported pharmacogenomic data for irbesartan was leveraged in the development of the PBPK model and collected clinical pharmacokinetic data for irbesartan was used for the validation of the model. Physicochemical and ADME properties of irbesartan were obtained from previously reported data, predicted by the modeling software, or optimized to fit the observed plasma concentration–time profiles. Model evaluation was performed by comparing the predicted plasma concentration–time profiles and pharmacokinetic parameters to the observed results. Predicted plasma concentration–time profiles were visually similar to observed profiles. Predicted AUCinf in CYP2C9*1/*3 and CYP2C9*1/*13 genotypes were increased by 1.54- and 1.62-fold compared to CYP2C9*1/*1 genotype, respectively. All fold error values for AUC and Cmax in non-genotyped and CYP2C9 genotyped models were within the two-fold error criterion. We properly established the PBPK model of irbesartan in different CYP2C9 genotypes. It can be used to predict the pharmacokinetics of irbesartan for personalized pharmacotherapy in individuals of various races, ages, and CYP2C9 genotypes.

Effects of CYP2C19 genetic polymorphism on the pharmacokinetics of tolperisone in healthy subjects

Chang-Keun Cho,Ji-Young Byeon,Pureum Kang,Hye-Jung Park,Eunvin Ko,Chou Yen Mu,Choon-Gon Jang,Seok-Yong Lee,Yun Jeong Lee 대한약학회 2023 Archives of Pharmacal Research Vol.46 No.2

Tolperisone hydrochloride is a centrally-acting muscle relaxant used for relieving spasticities of neurological origin and muscle spasms associated with painful locomotor diseases. It is metabolized to the inactive metabolite mainly by CYP2D6 and, to a lesser extent, by CYP2C19 and CYP1A2. In our previous study, the pharmacokinetics of tolperisone was significantly affected by the genetic polymorphism of CYP2D6, but the wide interindividual variation of tolperisone pharmacokinetics was not explained by genetic polymorphism of CYP2D6 alone. Thus, we studied the effects of CYP2C19 genetic polymorphism on tolperisone pharmacokinetics. Eighty-one subjects with different CYP2C19 genotypes received a single oral dose of 150 mg tolperisone with 240 mL of water, and blood samples were collected up to 12 h after dosing. The plasma concentration of tolperisone was measured by a liquid chromatography-tandem mass spectrometry system. The CYP2C19PM group had significantly higher Cmax and lower CL/F values than the CYP2C19EM and CYP2C19IM groups. The AUCinf of the CYP2C19PM group was 2.86-fold and 3.00-fold higher than the CYP2C19EM and CYP2C19IM groups, respectively. In conclusion, the genetic polymorphism of CYP2C19 significantly affected tolperisone pharmacokinetics.

Effects of CYP2D6*10 allele on the pharmacokinetics of tolperisone

Chang-Keun Cho,Ji-Young Byeon,Pureum Kang,Jung-In Park,Choon-Gon Jang,Seok-Yong Lee,Chang-Ik Choi,Jung-Woo Bae,Yun Jeong Lee 대한약학회 2023 Archives of Pharmacal Research Vol.46 No.1

Tolperisone, a muscle relaxant used for post-stroke spasticity, has been reported to have a very wide interindividual pharmacokinetic variability. It is metabolized mainly by CYP2D6 and, to a lesser extent, by CYP2C19 and CYP1A2. CYP2D6 is a highly polymorphic enzyme, and CYP2D6*wt/*wt, CYP2D6*wt/*10 and CYP2D6*10/*10 genotypes constitute more than 90% of the CYP2D6 genotypes in the Korean population. Thus, effects of the CYP2D6*10 on tolperisone pharmacokinetics were investigated in this study to elucidate the reasons for the wide interindividual variability. Oral tolperisone 150 mg was given to sixty-four healthy Koreans, and plasma concentrations of tolperisone were measured by liquid chromatography-tandem mass spectrometry (LC–MS/MS). The CYP2D6*10/*10 and CYP2D6*wt/*10 groups had significantly higher Cmax and lower CL/F values than the CYP2D6*wt/*wt group. The AUCinf of CYP2D6*10/*10 and CYP2D6*wt/*10 groups were 5.18-fold and 2.25-fold higher than the CYP2D6*wt/*wt group, respectively. There were considerable variations in the Cmax and AUC values within each genotype group, and the variations were greater as the activity of CYP2D6 decreased. These results suggest that the genetic polymorphism of CYP2D6 significantly affected tolperisone pharmacokinetics and factor(s) other than CYP2D6 may also have significant effects on the pharmacokinetics of tolperisone.

Physiologically based pharmacokinetic (PBPK) modeling of meloxicam in different CYP2C9 genotypes

Chang-Keun Cho,Hye-Jung Park,Pureum Kang,Sungmin Moon,Yun Jeong Lee,배정우,Choon-Gon Jang,이석용 대한약학회 2021 Archives of Pharmacal Research Vol.44 No.12

Meloxicam, a non-steroidal anti-infl ammatorydrug, is used for the treatment of rheumatoid arthritis andosteoarthritis. Cytochrome P450 (CYP) 2C9 and CYP3A4are major and minor enzymes involved in the metabolism ofmeloxicam. Impaired enzyme activity of CYP2C9 variantsincreases the plasma exposures of meloxicam and the riskof adverse events. The objective of our study is to developand validate the physiologically based pharmacokinetic(PBPK) model of meloxicam related to CYP2C9 geneticpolymorphism using the PK-Sim ® software. In vitro k cat ofCYP2C9 was optimized in diff erent CYP2C9 genotypes. Thedemographic and pharmacokinetic dataset for the developmentof the PBPK model was extracted from two previousclinical pharmacokinetic studies. Thirty-one clinical datasets,representing diff erent dose regimens and demographiccharacteristics, were utilized to validate the PBPK model. The shapes of simulated plasma concentration–time profi lesin each CYP2C9 genotype were visually similar to observedprofi les. The predicted exposures (AUC inf ) of meloxicamin CYP2C9*1/*3 , CYP2C9*1/*13 , and CYP2C9*3/*3genotypes were increased by 1.77-, 2.91-, and 8.35-fold compared to CYP2C9*1/*1 genotype, respectively. In alldatasets for the development and validations, fold errorsbetween predicted and observed pharmacokinetic parameterswere within the two-fold error criteria. As a result, the PBPKmodel was appropriately established and properly describedthe pharmacokinetics of meloxicam in diff erent CYP2C9genotypes. This study is expected to contribute to reducingthe risk of adverse events of meloxicam through optimizationof meloxicam dosing in diff erent CYP2C9 genotypes.

Physiologically based pharmacokinetic (PBPK) modelling of tamsulosin related to CYP2D6*10 allele

Chang-Keun Cho,Pureum Kang,Hye-Jung Park,Yun Jeong Lee,Jung-Woo Bae,Choon-Gon Jang,이석용 대한약학회 2021 Archives of Pharmacal Research Vol.44 No.11

Tamsulosin, a selective α1 -adrenoceptor blocker,is commonly used for alleviation of lower urinary tractsymptoms related to benign prostatic hyperplasia. Tamsulosinis predominantly metabolized by CYP3A4 andCYP2D6 enzymes, and several studies reported the eff ectsof CYP2D6 genetic polymorphism on the pharmacokineticsof tamsulosin. This study aims to develop and validatethe physiologically based pharmacokinetic (PBPK) modelof tamsulosin in CYP2D6*wt/*wt , CYP2D6*wt/*10 , andCYP2D6*10/*10 genotypes, using Simcyp® simulator. Physicochemical, and formulation properties and data forabsorption, distribution, metabolism and excretion were collectedfrom previous publications, predicted in the simulator,or optimized in diff erent CYP2D6 genotypes. The tamsulosinPBPK model in CYP2D6*wt/*wt and CYP2D6*wt/*10genotypes were developed based on the clinical pharmacokineticstudy where a single oral dose of 0.2 mg tamsulosinwas administered to 25 healthy Korean male volunteerswith CYP2D6*wt/*wt and CYP2D6*wt/*10 genotypes. Aprevious pharmacokinetic study was used to develop themodel in CYP2D6*10/*10 genotype. The developed modelwas validated using other clinical pharmacokinetic studiesnot used in development. The predicted exposures via the PBPK model in CYP2D6*wt/*10 and CYP2D6*10/*10 genotypewas 1.23- and 1.76-fold higher than CYP2D6*wt/*wtgenotype, respectively. The simulation profi les were visuallysimilar to the observed profi les, and fold errors of alldevelopment and validation datasets were included withinthe criteria. Therefore, the tamsulosin PBPK model in diff erentCYP2D6 genotypes with regards to CYP2D6*10 alleleswas appropriately established. Our model can contributeto the implementation of personalized pharmacotherapy ofpatients, appropriately predicting the pharmacokinetics oftamsulosin refl ecting their demographic and CYP2D6 genotypecharacteristics without unnecessary drug exposure.

Physiologically based pharmacokinetic (PBPK) modeling of piroxicam with regard to CYP2C9 genetic polymorphism

Chang-Keun Cho,Pureum Kang,Hye-Jung Park,Eunvin Ko,Chou Yen Mu,Yun Jeong Lee,Chang-Ik Choi,Hyung Sik Kim,Choon-Gon Jang,Jung-Woo Bae,Seok-Yong Lee 대한약학회 2022 Archives of Pharmacal Research Vol.45 No.5

Piroxicam is a non-steroidal anti-inflammatorydrug used to alleviate symptoms of osteoarthritis andrheumatoid arthritis. CYP2C9 genetic polymorphism significantly infl uences the pharmacokinetics of piroxicam. The objective of this study was to develop and validate thepiroxicam physiologically based pharmacokinetic (PBPK)model related to CYP2C9 genetic polymorphism. PK-Sim ®version 10.0 was used for the PBPK modeling. The PBPKmodel was evaluated by predicted and observed plasma concentration–time profi les, fold errors of predicted to observedpharmacokinetic parameters, and a goodness-of-fi t plot. Theturnover number (k cat ) of CYP2C9 was adjusted to capturethe pharmacokinetics of piroxicam in diff erent CYP2C9genotypes. The population PBPK model overall accuratelydescribed and predicted the plasma concentration–timeprofi les in diff erent CYP2C9 genotypes. In our simulations,predicted AUC inf in CYP2C9*1/*2 , CYP2C9*1/*3 , andCYP2C9*3/*3 genotypes were 1.83-, 2.07-, and 6.43-foldhigher than CYP2C9*1/*1 genotype, respectively. All fold error values for AUC, C max , and t 1/2 were included in theacceptance criterion with the ranges of 0.57–1.59, 0.63–1.39, and 0.65–1.51, respectively. The range of fold errorvalues for predicted versus observed plasma concentrationswas 0.11–3.13. 93.9% of fold error values were within thetwo-fold range. Average fold error, absolute average folderror, and root mean square error were 0.93, 1.27, and 0.72,respectively. Our model accurately captured the pharmacokineticalterations of piroxicam according to CYP2C9 geneticpolymorphism.

Physiologically based pharmacokinetic (PBPK) modeling of pitavastatin in relation to SLCO1B1 genetic polymorphism

Chang-Keun Cho,Ju Yeon Mo,Eunvin Ko,Pureum Kang,Choon-Gon Jang,Seok-Yong Lee,Yun Jeong Lee,Jung-Woo Bae,Chang-Ik Choi 대한약학회 2024 Archives of Pharmacal Research Vol.47 No.2

Pitavastatin, a potent 3-hydroxymethylglutaryl coenzyme A reductase inhibitor, is indicated for the treatment of hypercholesterolemiaand mixed dyslipidemia. Hepatic uptake of pitavastatin is predominantly occupied by the organic anion transportingpolypeptide 1B1 (OATP1B1) and solute carrier organic anion transporter family member 1B1 ( SLCO1B1 ) gene, which isa polymorphic gene that encodes OATP1B1. SLCO1B1 genetic polymorphism signifi cantly alters the pharmacokinetics ofpitavastatin. This study aimed to establish the physiologically based pharmacokinetic (PBPK) model to predict pitavastatinpharmacokinetics according to SLCO1B1 genetic polymorphism. PK-Sim ® version 10.0 was used to establish the wholebodyPBPK model of pitavastatin. Our pharmacogenomic data and a total of 27 clinical pharmacokinetic data with diff erentdose administration and demographic properties were used to develop and validate the model, respectively. Physicochemicalproperties and disposition characteristics of pitavastatin were acquired from previously reported data or optimized to capturethe plasma concentration–time profi les in diff erent SLCO1B1 diplotypes. Model evaluation was performed by comparing thepredicted pharmacokinetic parameters and profi les to the observed data. Predicted plasma concentration–time profi les werevisually similar to the observed profi les in the non-genotyped populations and diff erent SLCO1B1 diplotypes. All fold errorvalues for AUC and C max were included in the two fold range of observed values. Thus, the PBPK model of pitavastatin indiff erent SLCO1B1 diplotypes was properly established. The present study can be useful to individualize the dose administrationstrategy of pitavastatin in individuals with various ages, races, and SLCO1B1 diplotypes.

PBPK modeling to predict the pharmacokinetics of pantoprazole in different CYP2C19 genotypes

Chang-Keun Cho,Eunvin Ko,Ju Yeon Mo,Pureum Kang,Choon-Gon Jang,Seok-Yong Lee,Yun Jeong Lee,Jung-Woo Bae,Chang-Ik Choi 대한약학회 2024 Archives of Pharmacal Research Vol.47 No.1

Pantoprazole is used to treat gastroesophageal refl ux disease (GERD), maintain healing of erosive esophagitis (EE), andcontrol symptoms related to Zollinger–Ellison syndrome (ZES). Pantoprazole is mainly metabolized by cytochrome P450(CYP) 2C19, converting to 4′-demethyl pantoprazole. CYP2C19 is a genetically polymorphic enzyme, and the geneticpolymorphism aff ects the pharmacokinetics and/or pharmacodynamics of pantoprazole. In this study, we aimed to establishthe physiologically based pharmacokinetic (PBPK) model to predict the pharmacokinetics of pantoprazole in populationswith various CYP2C19 metabolic activities. A comprehensive investigation of previous reports and drug databases wasconducted to collect the clinical pharmacogenomic data, physicochemical data, and disposition properties of pantoprazole,and the collected data were used for model establishment. The model was evaluated by comparing the predicted plasmaconcentration–time profi les and/or pharmacokinetic parameters (AUC and C max ) with the clinical observation results. Thepredicted plasma concentration–time profi les in diff erent CYP2C19 phenotypes properly captured the observed profi les. All fold error values for AUC and C max were included in the two-fold range. Consequently, the minimal PBPK model forpantoprazole related to CYP2C19 genetic polymorphism was properly established and it can predict the pharmacokineticsof pantoprazole in diff erent CYP2C19 phenotypes. The present model can broaden the insight into the individualizedpharmacotherapy for pantoprazole.

디지털 복사기에서의 가는 선 검출 및 복원 방법

김창곤(Chang Gon Kim),배장현(Jang Hyeon Bae),김춘우(Choon-Woo Kim),박형준(Hyung Jun Park),강기민(Ki-Min Kang) 대한전기학회 2015 정보 및 제어 심포지엄 논문집 Vol.2015 No.10

Effects of CYP2C19 Genetic Polymorphisms on Atomoxetine Pharmacokinetics

Choi, Chang-Ik,Bae, Jung-Woo,Lee, Yun-Jeong,Lee, Hye-In,Jang, Choon-Gon,Lee, Seok-Yong by Lippincott Williams Wilkins. 2014 JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY Vol.34 No.1

ABSTRACT: Atomoxetine is a selective norepinephrine reuptake inhibitor indicated for the treatment of attention-deficit/hyperactivity disorder. Atomoxetine metabolism is mediated by CYP2D6 and CYP2C19. This study aimed to investigate the effect of the CYP2C19 genetic polymorphism on the pharmacokinetics of atomoxetine and its metabolites, 4-hydroxyatomoxetine and N-desmethylatomoxetine. A single 40-mg oral dose of atomoxetine was administered to 40 subjects with different CYP2C19 genotypes (all participants carried the CYP2D6*1/*10 genotype). Concentrations of atomoxetine and its metabolites were analyzed using high-performance liquid chromatography with tandem mass spectrometry in plasma samples that were collected up to 24 hours after drug intake. For atomoxetine, the CYP2C19 poor metabolizer (PM) group showed significantly increased maximum plasma concentration and AUC0−∞ (area under the plasma concentration-time curve from 0 to infinity) and decreased apparent oral clearance compared with samples of the CYP2C19 extensive metabolizer (EM) and intermediate metabolizer (IM) groups (P < 0.001 for all). The half-life of atomoxetine in the CYP2C19PM group was also significantly longer than in the other genotype groups (P < 0.01 for CYP2C19EM and P < 0.05 for CYP2C19IM groups). The maximum plasma concentration and AUC0−∞ of 4-hydroxyatomoxetine were significantly higher in the CYP2C19PM group compared with those in the CYP2C19EM and IM groups (P < 0.001 for CYP2C19EM and P < 0.05 for CYP2C19IM, respectively), whereas the corresponding values for N-desmethylatomoxetine in the CYP2C19PM group were significantly lower than those in the 2 genotype groups (P < 0.001 for both genotype groups). These results suggest that the genetic polymorphisms of CYP2C19 significantly affect the pharmacokinetics of atomoxetine.