Physiologically based pharmacokinetic modeling of candesartan related to CYP2C9 genetic polymorphism in adult and pediatric patients

Eui Hyun Jung; Chang Keun Cho; Pureum Kang; Hye Jung Park; Yun Jeong Lee; Jung Woo Bae; Chang Ik Choi; Choon Gon Jang; Seok Yong Lee

doi:10.1007/s12272-021-01363-1

Physiologically based pharmacokinetic modeling of candesartan related to CYP2C9 genetic polymorphism in adult and pediatric patients

Eui Hyun Jung, Chang Keun Cho, Pureum Kang, Hye Jung Park, Yun Jeong Lee, Jung Woo Bae, Chang Ik Choi, Choon Gon Jang, Seok Yong Lee

Department of Pharmacy

Research output: Contribution to journal › Article › peer-review

16 Scopus citations

Abstract

Candesartan cilexetil is an angiotensin II receptor blocker and it is widely used to treat hypertension and heart failure. This drug is a prodrug that rapidly converts to candesartan after oral administration. Candesartan is metabolized by cytochrome P450 2C9 (CYP2C9) enzyme or uridine diphosphate glucurinosyltransferase 1A3, or excreted in an unchanged form through urine, biliary tract and feces. We investigated the effect of genetic polymorphism of CYP2C9 enzyme on drug pharmacokinetics using physiologically based pharmacokinetic (PBPK) modeling. In addition, by introducing the age and ethnicity into the model, we developed a model that can propose an appropriate dosage regimen taking into account the individual characteristics of each patient. To evaluate the suitability of the model, the results of a clinical trial on twenty-two healthy Korean subjects and their CYP2C9 genetic polymorphism data was applied. In this study, PK-Sim® was used to develop the PBPK model of candesartan.

Original language	English
Pages (from-to)	1109-1119
Number of pages	11
Journal	Archives of Pharmacal Research
Volume	44
Issue number	12
DOIs	https://doi.org/10.1007/s12272-021-01363-1
State	Published - Dec 2021

Keywords

Candesartan
CYP2C9
Genotype
PBPK
Polymorphism

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title = "Physiologically based pharmacokinetic modeling of candesartan related to CYP2C9 genetic polymorphism in adult and pediatric patients",

abstract = "Candesartan cilexetil is an angiotensin II receptor blocker and it is widely used to treat hypertension and heart failure. This drug is a prodrug that rapidly converts to candesartan after oral administration. Candesartan is metabolized by cytochrome P450 2C9 (CYP2C9) enzyme or uridine diphosphate glucurinosyltransferase 1A3, or excreted in an unchanged form through urine, biliary tract and feces. We investigated the effect of genetic polymorphism of CYP2C9 enzyme on drug pharmacokinetics using physiologically based pharmacokinetic (PBPK) modeling. In addition, by introducing the age and ethnicity into the model, we developed a model that can propose an appropriate dosage regimen taking into account the individual characteristics of each patient. To evaluate the suitability of the model, the results of a clinical trial on twenty-two healthy Korean subjects and their CYP2C9 genetic polymorphism data was applied. In this study, PK-Sim{\textregistered} was used to develop the PBPK model of candesartan.",

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author = "Jung, {Eui Hyun} and Cho, {Chang Keun} and Pureum Kang and Park, {Hye Jung} and Lee, {Yun Jeong} and Bae, {Jung Woo} and Choi, {Chang Ik} and Jang, {Choon Gon} and Lee, {Seok Yong}",

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year = "2021",

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doi = "10.1007/s12272-021-01363-1",

language = "English",

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T1 - Physiologically based pharmacokinetic modeling of candesartan related to CYP2C9 genetic polymorphism in adult and pediatric patients

AU - Jung, Eui Hyun

AU - Cho, Chang Keun

AU - Kang, Pureum

AU - Park, Hye Jung

AU - Lee, Yun Jeong

AU - Bae, Jung Woo

AU - Choi, Chang Ik

AU - Jang, Choon Gon

AU - Lee, Seok Yong

PY - 2021/12

Y1 - 2021/12

N2 - Candesartan cilexetil is an angiotensin II receptor blocker and it is widely used to treat hypertension and heart failure. This drug is a prodrug that rapidly converts to candesartan after oral administration. Candesartan is metabolized by cytochrome P450 2C9 (CYP2C9) enzyme or uridine diphosphate glucurinosyltransferase 1A3, or excreted in an unchanged form through urine, biliary tract and feces. We investigated the effect of genetic polymorphism of CYP2C9 enzyme on drug pharmacokinetics using physiologically based pharmacokinetic (PBPK) modeling. In addition, by introducing the age and ethnicity into the model, we developed a model that can propose an appropriate dosage regimen taking into account the individual characteristics of each patient. To evaluate the suitability of the model, the results of a clinical trial on twenty-two healthy Korean subjects and their CYP2C9 genetic polymorphism data was applied. In this study, PK-Sim® was used to develop the PBPK model of candesartan.

AB - Candesartan cilexetil is an angiotensin II receptor blocker and it is widely used to treat hypertension and heart failure. This drug is a prodrug that rapidly converts to candesartan after oral administration. Candesartan is metabolized by cytochrome P450 2C9 (CYP2C9) enzyme or uridine diphosphate glucurinosyltransferase 1A3, or excreted in an unchanged form through urine, biliary tract and feces. We investigated the effect of genetic polymorphism of CYP2C9 enzyme on drug pharmacokinetics using physiologically based pharmacokinetic (PBPK) modeling. In addition, by introducing the age and ethnicity into the model, we developed a model that can propose an appropriate dosage regimen taking into account the individual characteristics of each patient. To evaluate the suitability of the model, the results of a clinical trial on twenty-two healthy Korean subjects and their CYP2C9 genetic polymorphism data was applied. In this study, PK-Sim® was used to develop the PBPK model of candesartan.

KW - Candesartan

KW - CYP2C9

KW - Genotype

KW - PBPK

KW - Polymorphism

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DO - 10.1007/s12272-021-01363-1

M3 - Article

C2 - 34817825

AN - SCOPUS:85120654816

SN - 0253-6269

VL - 44

SP - 1109

EP - 1119

JO - Archives of Pharmacal Research

JF - Archives of Pharmacal Research

IS - 12

ER -

Physiologically based pharmacokinetic modeling of candesartan related to CYP2C9 genetic polymorphism in adult and pediatric patients

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