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.
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References
Abduljalil KCT, Humphries H, Rostami-Hodjegan A (2014) Deciding on success criteria for predictability of pharmacokinetic parameters from in vitro studies: an analysis based on in vivo observations. Drug Metab Dispos 42:1478–1484. https://doi.org/10.1124/dmd.114.058099
AstraZeneca (2005) Atacan® (candesartan cilexetil) prescribing information. [Online] Available from https://www.accessdata.fda.gov/drugsatfda_docs/label/2005/020838s022lbl.pdf. Accessed 1 Oct 2021
Bae JW, Kim HK, Kim JH, Yang SI, Kim MJ, Jang CG, Park YS, Lee SY (2005) Allele and genotype frequencies of CYP2C9 in a Korean population. Br J Clin Pharmacol 60(4):418–422. https://doi.org/10.1111/j.1365-2125.2005.02448.x
Bae JW, Choi CI, Kim MJ, Oh DH, Keum SK, Park JI, Kim BH, Bang HK, Oh SG, Kang BS, Park HJ, Kim HD, Ha JH, Shin HJ, Kim YH, Na HS, Chung MW, Jang CG, Lee SY (2011) Frequency of CYP2C9 alleles in Koreans and their effects on losartan pharmacokinetics. Acta Pharmacol Sin 32(10):1303–1308. https://doi.org/10.1038/aps.2011.100
Bae JW, Oh KY, Yoon SJ, Shin HB, Jung EH, Cho CK, Lim CW, Kang P, Choi CI, Jang CG, Lee SY, Lee YJ (2020) Effects of CYP2D6 genetic polymorphism on the pharmacokinetics of metoclopramide. Arch Pharm Res 43(11):1207–1213. https://doi.org/10.1007/s12272-020-01293-4
Buter H, Navis GY, Woittiez AJ, de Zeeuw D, de Jong PE (1999) Pharmacokinetics and pharmacodynamics of candesartan cilexetil in patients with normal to severely impaired renal function. Eur J Clin Pharmacol 54(12):953–958. https://doi.org/10.1007/s002280050581
Byeon JY, Kim YH, Kim SH, Lee CM, Jung EH, Chae WK, Jang CG, Lee SY, Lee YJ (2018) The influences of CYP2C9*1/*3 genotype on the pharmacokinetics of zolpidem. Arch Pharm Res 41(9):931–936. https://doi.org/10.1007/s12272-018-1070-y
Byeon JY, Lee CM, Lee YJ, Kim YH, Kim SH, Jung EH, Chae WK, Lee YJ, Jang CG, Lee SY (2019) Influence of CYP2D6 genetic polymorphism on pharmacokinetics of active moiety of tolterodine. Arch Pharm Res 42(2):182–190. https://doi.org/10.1007/s12272-018-1099-y
Cabaleiro T, Román M, Ochoa D, Talegón M, Prieto-Pérez R, Wojnicz A, López-Rodríguez R, Novalbos J, Abad-Santos F (2013) Evaluation of the relationship between sex, polymorphisms in CYP2C8 and CYP2C9, and pharmacokinetics of angiotensin receptor blockers. Drug Metab Dispos 41(1):224–229. https://doi.org/10.1124/dmd.112.046292
Chan SC, Liu CL, Lo CM, Lam BK, Lee EW, Wong Y, Fan ST (2006) Estimating liver weight of adults by body weight and gender. World J Gastroenterol 12(14):2217–2222. https://doi.org/10.3748/wjg.v12.i4.2217
Chetty M, Rose RH, Abduljalil K, Patel N, Lu G, Cain T, Jamei M, Rostami-Hodjegan A (2014) Applications of linking PBPK and PD models to predict the impact of genotypic variability, formulation differences, differences in target binding capacity and target site drug concentrations on drug responses and variability. Front Pharmacol 26(5):258. https://doi.org/10.3389/fphar.2014.00258
Fu-Gui L, Lu-Nan Y, Bo L, Yong Z, Tian-Fu W, Ming-Qing X, Wen-Tao W, Zhe-Yu C (2009) Estimation of standard liver volume in Chinese adult living donors. Transplant Proc 41(10):4052–4056. https://doi.org/10.1016/j.transproceed.2009.08.079
García-Martín E, Martínez C, Ladero JM, Agúndez JA (2006) Interethnic and intraethnic variability of CYP2C8 and CYP2C9 polymorphisms in healthy individuals. Mol Diagn Ther 10(1):29–40. https://doi.org/10.1007/BF03256440
Gleiter CH, Mörike KE (2002) Clinical pharmacokinetics of candesartan. Clin Pharmacokinet 41(1):7–17. https://doi.org/10.2165/00003088-200241010-00002
Hanatani T, Fukuda T, Ikeda M, Imaoka S, Hiroi T, Funae Y, Azuma J (2001) CYP2C9*3 influences the metabolism and the drug-interaction of candesartan in vitro. Pharmacogenomics J 1(4):288–292. https://doi.org/10.1038/sj.tpj.6500063
Hoogkamer JF, Kleinbloesem CH, Ouwerkerk M, Högemann A, Nokhodian A, Kirch W, Weidekamm E (1998) Pharmacokinetics and safety of candesartan cilexetil in subjects with normal and impaired liver function. Eur J Clin Pharmacol 54(4):341–345. https://doi.org/10.1007/s002280050471
Hoy SM, Keating GM (2010) Candesartan cilexetil: in children and adolescents aged 1 to <17 years with hypertension. Am J Cardiovasc Drugs 10(5):335–342. https://doi.org/10.2165/11206300-000000000-00000
Jameson JL, Longo DL (2015) Precision medicine–personalized, problematic, and promising. N Engl J Med 372(23):2229–2234. https://doi.org/10.1056/NEJMsb1503104
Jeon JY, Im YJ, Kim Y, Han SM, Jo MJ, Shin DH, Yoo JS, Moon BK, Kim BK, Lee BH, Choi YH, Cho BS, Jang HY, Chae SW, Kim MG (2013) Pharmacokinetic properties and bioequivalence of candesartan cilexetil in Korean healthy volunteers. Drug Dev Ind Pharm. https://doi.org/10.3109/03639045.2012.725732
Johnson TN, Tucker GT, Tanner MS, Rostami-Hodjegan A (2005) Changes in liver volume from birth to adulthood: a meta-analysis. Liver Transplant 11(12):1481–1493. https://doi.org/10.1002/lt.20519
Jung EH, Lee CM, Byeon JY, Shin HB, Oh KY, Cho CK, Lim CW, Jang CG, Lee SY, Lee YJ (2020a) Relationship between plasma exposure of zolpidem and CYP2D6 genotype in healthy Korean subjects. Arch Pharm Res 43(9):976–981. https://doi.org/10.1007/s12272-020-01250-1
Jung EH, Lee YJ, Kim DH, Kang P, Lim CW, Cho CK, Jang CG, Lee SY, Bae JW (2020b) Effects of paroxetine on the pharmacokinetics of atomoxetine and its metabolites in different CYP2D6 genotypes. Arch Pharm Res 43(12):1356–1363. https://doi.org/10.1007/s12272-020-01300-8
Kearns GL, Abdel-Rahman SM, Alander SW, Blowey DL, Leeder JS, Kauffman RE (2003) Developmental pharmacology–drug disposition, action, and therapy in infants and children. N Engl J Med 349(12):1157–1167. https://doi.org/10.1056/NEJMra035092
Kim SW, Jung SS, Lee AR, Son JW (2012) Pharmaceutical formulation for treating cardiovascular disease. Republic of Korea patent KR-10-1205633. 2012 Nov 21
Kim SH, Kim DH, Byeon JY, Kim YH, Kim DH, Lim HJ, Lee CM, Whang SS, Choi CI, Bae JW, Lee YJ, Jang CG, Lee SY (2017) Effects of CYP2C9 genetic polymorphisms on the pharmacokinetics of celecoxib and its carboxylic acid metabolite. Arch Pharm Res 40(3):382–390. https://doi.org/10.1007/s12272-016-0861-2
Kim JH, Yun S, Hwang SS, Shim JO, Chae HW, Lee YJ, Lee JH, Kim SC, Lim D, Yang SW, Oh K, Moon JS, Committee for the Development of Growth Standards for Korean Children and Adolescents, Committee for School Health and Public Health Statistics, the Korean Pediatric Society, Division of Health and Nutrition Survey, Korea Centers for Disease Control and Prevention (2018) The 2017 Korean National Growth Charts for children and adolescents: development, improvement, and prospects. Korean J Pediatr 61(5):135–149. https://doi.org/10.3345/kjp.2018.61.5.135
Kim Y, Hatley O, Rhee SJ, Yi S, Lee HA, Yoon S, Chung JY, Yu KS, Lee H (2019) Development of a Korean-specific virtual population for physiologically based pharmacokinetic modelling and simulation. Biopharm Drug Dispos 40(3–4):135–150. https://doi.org/10.1002/bdd.2178
Kim YH, Kang P, Cho CK, Jung EH, Park HJ, Lee YJ, Bae JW, Jang CG, Lee SY (2021) Physiologically based pharmacokinetic (PBPK) modeling for prediction of celecoxib pharmacokinetics according to CYP2C9 genetic polymorphism. Arch Pharm Res 44(7):713–724. https://doi.org/10.1007/s12272-021-01346-2
König IR, Fuchs O, Hansen G, von Mutius E, Kopp MV (2017) What is precision medicine? Eur Respir J 50(4):1700391. https://doi.org/10.1183/13993003.00391-2017
Kumar V, Brundage RC, Oetting WS, Leppik IE, Tracy TS (2008) Differential genotype dependent inhibition of CYP2C9 in humans. Drug Metab Dispos 36(7):1242–1248. https://doi.org/10.1124/dmd.108.020396
Lee YJ, Byeon JY, Kim YH, Kim SH, Choi CI, Bae JW, Sohn UD, Jang CG, Lee J, Lee SY (2015) Effects of CYP2C9*1/*3 genotype on the pharmacokinetics of flurbiprofen in Korean subjects. Arch Pharm Res 38(6):1232–1237. https://doi.org/10.1007/s12272-015-0580-0
Lee CM, Jung EH, Byeon JY, Kim SH, Jang CG, Lee YJ, Lee SY (2019) Effects of steady-state clarithromycin on the pharmacokinetics of zolpidem in healthy subjects. Arch Pharm Res 42(12):1101–1106. https://doi.org/10.1007/s12272-019-01201-5
Lesko LJ, Schmidt S (2012) Individualization of drug therapy: history, present state, and opportunities for the future. Clin Pharmacol Ther 92(4):458–466. https://doi.org/10.1038/clpt.2012.113
Lukacova V, Goelzer P, Reddy M, Greig G, Reigner B, Parrott N (2016) A physiologically based pharmacokinetic model for ganciclovir and its prodrug valganciclovir in adults and children. AAPS J 18(6):1453–1463. https://doi.org/10.1208/s12248-016-9956-4
Malerczyk C, Fuchs B, Belz GG, Roll S, Butzer R, Breithaupt-Grögler K, Herrmann V, Magin SG, Högemann A, Voith B, Mutschler E (1998) Angiotensin II antagonism and plasma radioreceptor-kinetics of candesartan in man. Br J Clin Pharmacol 45(6):567–573. https://doi.org/10.1046/j.1365-2125.1998.00722.x
Mizutani T (2003) PM frequencies of major CYPs in Asians and Caucasians. Drug Metab Rev 35(2–3):99–106. https://doi.org/10.1081/dmr-120023681
Nakai K, Habano W, Nakai K, Fukushima N, Suwabe A, Moriya S, Osano K, Gurwitz D (2005) Ethnic differences in CYP2C9*2 (Arg144Cys) and CYP2C9*3 (Ile359Leu) genotypes in Japanese and Israeli populations. Life Sci 78(1):107–111. https://doi.org/10.1016/j.lfs.2005.04.049
Nishimuta H, Houston JB, Galetin A (2014) Hepatic, intestinal, renal, and plasma hydrolysis of prodrugs in human, cynomolgus monkey, dog, and rat: implications for in vitro-in vivo extrapolation of clearance of prodrugs. Drug Metab Dispos 42(9):1522–1531. https://doi.org/10.1124/dmd.114.057372
Noetzli M, Eap CB (2013) Pharmacodynamic, pharmacokinetic and pharmacogenetic aspects of drugs used in the treatment of Alzheimer’s disease. Clin Pharmacokinet 52(4):225–241. https://doi.org/10.1007/s40262-013-0038-9
Patel R, Palmer JL, Joshi S, Di Ció GA, Esquivel F (2017) Pharmacokinetic and bioequivalence studies of a newly developed branded generic of candesartan cilexetil tablets in healthy volunteers. Clin Pharmacol Drug Dev 6(5):492–498. https://doi.org/10.1002/cpdd.321
Rodgers T, Rowland M (2006) Physiologically based pharmacokinetic modelling 2: predicting the tissue distribution of acids, very weak bases, neutrals and zwitterions. J Pharm Sci 95(6):1238–1257. https://doi.org/10.1002/jps.20502
Rodgers T, Leahy D, Rowland M (2005) Physiologically based pharmacokinetic modeling 1: predicting the tissue distribution of moderate-to-strong bases. J Pharm Sci 94(6):1259–1276. https://doi.org/10.1002/jps.20322
Schaefer F, van de Walle J, Zurowska A, Gimpel C, van Hoeck K, Drozdz D, Montini G, Bagdasorova IV, Sorof J, Sugg J, Teng R, Hainer JW, Candesartan in Children with Hypertension Investigators (2010) Efficacy, safety and pharmacokinetics of candesartan cilexetil in hypertensive children from 1 to less than 6 years of age. J Hypertens 28(5):1083–1090. https://doi.org/10.1097/HJH.0b013e328336b86b
Shi ZR, Yan LN, Li B, Wen TF (2009) Evaluation of standard liver volume formulae for Chinese adults. World J Gastroenterol 15(32):4062–4066. https://doi.org/10.3748/wjg.15.4062
Shimada T, Yamazaki H, Mimura M, Inui Y, Guengerich FP (1994) Interindividual variations in human liver cytochrome P-450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals: studies with liver microsomes of 30 Japanese and 30 Caucasians. J Pharmacol Exp Ther 270(1):414–423
Shin HS, Chung BH, Lee SE, Kim WJ, Ha HI, Yang CW (2009) Measurement of kidney volume with multi-detector computed tomography scanning in young Korean. Yonsei Med J 50(2):262–265. https://doi.org/10.3349/ymj.2009.50.2.262
Shin HB, Jung EH, Kang P, Lim CW, Oh KY, Cho CK, Lee YJ, Choi CI, Jang CG, Lee SY, Bae JW (2020) ABCB1 c.2677G>T/c.3435C>T diplotype increases the early-phase oral absorption of losartan. Arch Pharm Res 43(11):1187–1196. https://doi.org/10.1007/s12272-020-01294-3
Sy SK, Asin-Prieto E, Derendorf H, Samara E (2014) Predicting pediatric age-matched weight and body mass index. AAPS J 16(6):1372–1379. https://doi.org/10.1208/s12248-014-9657-9
Thelen K, Coboeken K, Willmann S, Burghaus R, Dressman JB, Lippert J (2011) Evolution of a detailed physiological model to simulate the gastrointestinal transit and absorption process in humans, part 1: oral solutions. J Pharm Sci 100(12):5324–5345. https://doi.org/10.1002/jps.22726
Tjandrawinata RR, Setiawati E, Yunaidi DA, Simanjuntak R, Santoso ID, Susanto LW (2013) Bioequivalence study of two formulations of candesartan cilexetil tablet in healthy subjects under fasting conditions. Drug Des Dev Ther 7:841–847. https://doi.org/10.2147/DDDT.S47272
Trachtman H, Hainer JW, Sugg J, Teng R, Sorof JM, Radcliffe J, Candesartan in Children with Hypertension (CINCH) Investigators (2008) Efficacy, safety, and pharmacokinetics of candesartan cilexetil in hypertensive children aged 6 to 17 years. J Clin Hypertens (Greenwich) 10(10):743–750. https://doi.org/10.1111/j.1751-7176.2008.00022.x
Yu HC, You H, Lee H, Jin ZW, Moon JI, Cho BH (2004) Estimation of standard liver volume for liver transplantation in the Korean population. Liver Transplant 10(6):779–783. https://doi.org/10.1002/lt.20188
Yuan D, Lu T, Wei YG, Li B, Yan LN, Zeng Y, Wen TF, Zhao JC (2008) Estimation of standard liver volume for liver transplantation in the Chinese population. Transplant Proc 40(10):3536–3540. https://doi.org/10.1016/j.transproceed.2008.07.135
Zhou SF, Zhou ZW, Yang LP, Cai JP (2009) Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem 16(27):3480–3675. https://doi.org/10.2174/092986709789057635
Duan P, Zhao P, Zhang L (2017) Physiologically Based Pharmacokinetic (PBPK) modeling of pitavastatin and atorvastatin to predict Drug-Drug Interactions (DDIs). Eur J Drug Metab Pharmacokinet 42(4):689–705. https://doi. org/10. 1007/s13318-016-0383-9
Laizure SC, Herring V, Hu Z, Witbrodt K, Parker RB (2013) The role of human carboxylesterases in drug metabolism: have we overlooked their importance? Pharmacotherapy 33(2):210-22. doi: 10.1002/phar.1194.
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This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT, and Future Planning (NRF-2019R1A2C1004582).
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Jung, E.H., Cho, CK., Kang, P. et al. Physiologically based pharmacokinetic modeling of candesartan related to CYP2C9 genetic polymorphism in adult and pediatric patients. Arch. Pharm. Res. 44, 1109–1119 (2021). https://doi.org/10.1007/s12272-021-01363-1
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DOI: https://doi.org/10.1007/s12272-021-01363-1