Abstract
Background
International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) guidelines emphasize the need for better understanding of the influence of ethnicity on drug response to minimize duplication of clinical studies, thereby expediting drug approval.
Objectives
We have developed a Chinese database for the prediction of differences in the population kinetics of drugs mainly metabolized by cytochromes P450 (CYPs) relative to Caucasian populations. Such predictions should help to inform the need for duplication of in vivo pharmacokinetic studies in the two ethnic groups and the design of such studies.
Methods
Demographic and physiological data for Chinese, along with information on CYP abundances and the frequencies of associated genetic polymorphisms in Chinese, were collated from literature sources and incorporated within the Simcyp Population-based Simulator® (v11.1). Default Simcyp parameter values for a virtual Caucasian population and for model compounds metabolized principally by specific CYPs were used as the point of reference. The drugs and the main CYPs involved in their metabolism were phenacetin (CYP1A2), desipramine (CYP2D6), tolbutamide (CYP2C9), omeprazole (CYP2C19), and alprazolam and midazolam (CYP3A). Hydroxy bupropion formation was used as a more sensitive marker of CYP2B6 activity than bupropion kinetics. Observed plasma drug concentration–time profiles and pharmacokinetic parameters after oral and, where possible, intravenous dosing were obtained from published in vivo studies in both Chinese and Caucasian subjects. Virtual subjects generated within Simcyp were matched to the subjects used in the in vivo studies with respect to age, sex, dosage and, where possible, CYP phenotype frequency. Predicted and observed plasma drug concentrations and weight-normalized clearances were compared between the ethnic groups.
Results
Significant differences were identified between Chinese and Caucasian populations in the frequency of CYP2C19 poor metabolizers (PMs) [Chinese 13 %; Caucasian 2.4 %], CYP2D6 PMs and intermediate metabolizers (IMs) [Chinese PMs 0.3 %, IMs 39 %; Caucasian PMs 8 %, IMs <1 %], the hepatic abundance of CYP2C19 (mean values: Chinese 8 pmol/mg; Caucasian 14 pmol/mg) and liver weight (mean values: Chinese 1198 g; Caucasian 1603 g). The observed plasma drug concentration–time profiles and weight-normalized clearances were predicted with reasonable accuracy (100 % within twofold; 89 % within 1.5-fold) in both ethnic groups. The predicted phenacetin, tolbutamide, omeprazole, desipramine, midazolam (intravenous), midazolam (oral), alprazolam (intravenous) and alprazolam (oral) clearances were 36, 25, 51, 43, 24, 17, 21 and 22 % lower, respectively, in Chinese than in Caucasians; the observed clearances were 28, 2, 75, 42, 19, 62, 20 and 21 % lower, respectively. Predicted and observed formation of hydroxy bupropion was lower in Caucasians than in Chinese (6 and 20 %, respectively). Differences between ethnic groups were less after normalization for body weight.
Conclusion
The results of this study indicate the value of simulation based on mechanistic physiologically based pharmacokinetic modelling (PBPK) in anticipating the likely extent of any differences in the kinetics of CYP substrates in Chinese and Caucasian populations arising from demographic, physiological and genetic differences.
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References
Kudrin A. Challenges in the clinical development requirements for the marketing authorization of new medicines in southeast Asia. J Clin Pharmacol. 2009;49(3):268–80.
Emerging pharmaceutical market in China—forecast to become the world’s third-largest pharmaceutical market by 2013. http://www.marketresearch.com/GBI-Research-v3759/Emerging-Pharmaceutical-China-Forecast-Largest-6564799/. Accessed 23 May 2013.
Malinowski HJ, Westelinck A, Sato J, Ong T. Same drug, different dosing: differences in dosing for drugs approved in the United States, Europe, and Japan. J Clin Pharmacol. 2008;48(8):900–8.
Rostami-Hodjegan A, Tucker GT. Simulation and prediction of in vivo drug metabolism in human populations from in vitro data. Nat Rev Drug Discov. 2007;6(2):140–8.
Rowland M, Peck C, Tucker G. Physiologically-based pharmacokinetics in drug development and regulatory science. Annu Rev Pharmacol Toxicol. 2011;51:45–73.
Kim K, Johnson JA, Derendorf H. Differences in drug pharmacokinetics between East Asians and Caucasians and the role of genetic polymorphisms. J Clin Pharmacol. 2004;44(10):1083–105.
Inoue S, Howgate EM, Rowland-Yeo K, Shimada T, Yamazaki H, Tucker GT, et al. Prediction of in vivo drug clearance from in vitro data. II: Potential inter-ethnic differences. Xenobiotica. 2006;36(6):499–513.
Jamei M, Marciniak S, Feng K, Barnett A, Tucker G, Rostami-Hodjegan A. The Simcyp population-based ADME simulator. Expert Opin Drug Metab Toxicol. 2009;5(2):211–23.
Rowland Yeo K, Jamei M, Yang J, Tucker GT, Rostami-Hodjegan A. Physiologically based mechanistic modelling to predict complex drug–drug interactions involving simultaneous competitive and time-dependent enzyme inhibition by parent compound and its metabolite in both liver and gut—the effect of diltiazem on the time-course of exposure to triazolam. Eur J Pharm Sci. 2010;39(5):298–309.
Rostami-Hodjegan A, Tucker GT. ‘In silico’ simulations to assess the ‘in vivo’ consequences of ‘in vitro’ metabolic drug–drug interactions. Drug Discov Today Technol. 2004;1:441–8.
Jamei M, Turner D, Yang J, Neuhoff S, Polak S, Rostami-Hodjegan A, et al. Population-based mechanistic prediction of oral drug absorption. AAPS J. 2009;11(2):225–37.
CHNS. China Health and Nutrition Survey. http://www.cpc.unc.edu/projects/china. Accessed 23 May 2013.
Yu CY, Lo YH, Chiou WK. The 3D scanner for measuring body surface area: a simplified calculation in the Chinese adult. Appl Ergon. 2003;34(3):273–8.
DuBois D, DuBois E. A formula to estimate the approximate surface area if height and weight be known. Arch Intern Med. 1916;17:863.
Howgate EM, Rowland Yeo K, Proctor NJ, Tucker GT, Rostami-Hodjegan A. Prediction of in vivo drug clearance from in vitro data. I: Impact of inter-individual variability. Xenobiotica. 2006;36(6):473–97.
Jamei M, Dickinson GL, Rostami-Hodjegan A. A framework for assessing inter-individual variability in pharmacokinetics using virtual human populations and integrating general knowledge of physical chemistry, biology, anatomy, physiology and genetics: a tale of ‘bottom-up’ vs ‘top-down’ recognition of covariates. Drug Metab Pharmacokinet. 2009;24(1):53–75.
Johnson TN, Tucker GT, Tanner MS, Rostami-Hodjegan A. Changes in liver volume from birth to adulthood: a meta-analysis. Liver Transplant. 2005;11(12):1481–93.
Heinemann A, Wischhusen F, Puschel K, Rogiers X. Standard liver volume in the Caucasian population. Liver Transplant Surg. 1999;5(5):366–8.
Chan SC, Liu CL, Lo CM, Lam BK, Lee EW, Wong Y, et al. Estimating liver weight of adults by body weight and gender. World J Gastroenterol. 2006;12(14):2217–22.
Shi ZR, Yan LN, Li B, Wen TF. Evaluation of standard liver volume formulae for Chinese adults. World J Gastroenterol. 2009;15(32):4062–6.
Yuan D, Lu T, Wei YG, Li B, Yan LN, Zeng Y, et al. Estimation of standard liver volume for liver transplantation in the Chinese population. Transplant Proc. 2008;40(10):3536–40.
Fu-Gui L, Lu-Nan Y, Bo L, Yong Z, Tian-Fu W, Ming-Qing X, et al. Estimation of standard liver volume in Chinese adult living donors. Transplant Proc. 2009;41(10):4052–6.
Chou YH, Tiu CM, Pan HB, Chang T, Su YG. The measurement of spleno-portal venous and hepatic arterial blood flow in normal adults using duplex ultrasound—a preliminary report. Chin Med J. 1985;35:343–9.
Li J, Yang J, Jiang L. Hepatic blood flow in liver: clinical application of CT dynamic perfusion. J Clin Radiol. 2005;24(2):130–4.
Barter ZE, Bayliss MK, Beaune PH, Boobis AR, Carlile DJ, Edwards RJ, et al. Scaling factors for the extrapolation of in vivo metabolic drug clearance from in vitro data: reaching a consensus on values of human microsomal protein and hepatocellularity per gram of liver. Curr Drug Metab. 2007;8(1):33–45.
Barter ZE, Chowdry JE, Harlow JR, Snawder JE, Lipscomb JC, Rostami-Hodjegan A. Covariation of human microsomal protein per gram of liver with age: absence of influence of operator and sample storage may justify interlaboratory data pooling. Drug Metab Dispos. 2008;36(12):2405–9.
Paine MF, Khalighi M, Fisher JM, Shen DD, Kunze KL, Marsh CL, et al. Characterization of interintestinal and intraintestinal variations in human CYP3A-dependent metabolism. J Pharmacol Exp Ther. 1997;283(3):1552–62.
Rowland Yeo K, Rostami-Hodjegan A, Tucker GT. Abundance of cytochromes P450 in human liver: a meta-analysis. Br J Clin Pharmacol. 2004;57:687–8.
Cubitt HE, Yeo KR, Howgate EM, Rostami-Hodjegan A, Barter ZE. Sources of interindividual variability in IVIVE of clearance: an investigation into the prediction of benzodiazepine clearance using a mechanistic population-based pharmacokinetic model. Xenobiotica. 2011;41(8):623–38.
Shu Y, Wang LS, Xiao WM, Wang W, Huang SL, Zhou HH. Probing CYP2C19 and CYP3A4 activities in Chinese liver microsomes by quantification of 5-hydroxyomeprazole and omeprazole sulphone. Acta Pharmacol Sin. 2000;21(8):753–8.
Shu Y, Cheng ZN, Liu ZQ, Wang LS, Zhu B, Huang SL, et al. Interindividual variations in levels and activities of cytochrome P-450 in liver microsomes of Chinese subjects. Acta Pharmacol Sin. 2001;22(3):283–8.
Yang J, He MM, Niu W, Wrighton SA, Li L, Liu Y, et al. Metabolic capabilities of cytochrome P450 enzymes in Chinese liver microsomes compared with those in Caucasian liver microsomes. Br J Clin Pharmacol. 2012;73(2):268–84.
Shimada T, Yamazaki H, Mimura M, Inui Y, Guengerich FP. 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. 1994;270(1):414–23.
Yue QY, Svensson JO, Sjoqvist F, Sawe J. A comparison of the pharmacokinetics of codeine and its metabolites in healthy Chinese and Caucasian extensive hydroxylators of debrisoquine. Br J Clin Pharmacol. 1991;31(6):643–7.
Barter ZE, Perrett HF, Yeo KR, Allorge D, Lennard MS, Rostami-Hodjegan A. Determination of a quantitative relationship between hepatic CYP3A5*1/*3 and CYP3A4 expression for use in the prediction of metabolic clearance in virtual populations. Biopharm Drug Dispos. 2010;31(8–9):516–32.
Paine MF, Hart HL, Ludington SS, Haining RL, Rettie AE, Zeldin DC. The human intestinal cytochrome P450 “pie”. Drug Metab Dispos. 2006;34(5):880–6.
Lamba V, Lamba J, Yasuda K, Strom S, Davila J, Hancock ML, et al. Hepatic CYP2B6 expression: gender and ethnic differences and relationship to CYP2B6 genotype and CAR (constitutive androstane receptor) expression. J Pharmacol Exp Ther. 2003;307(3):906–22.
Scordo MG, Aklillu E, Yasar U, Dahl ML, Spina E, Ingelman-Sundberg M. Genetic polymorphism of cytochrome P450 2C9 in a Caucasian and a black African population. Br J Clin Pharmacol. 2001;52(4):447–50.
Zackrisson AL, Holmgren P, Gladh AB, Ahlner J, Lindblom B. Fatal intoxication cases: cytochrome P450 2D6 and 2C19 genotype distributions. Eur J Clin Pharmacol. 2004;60(8):547–52.
Lin YS, Dowling AL, Quigley SD, Farin FM, Zhang J, Lamba J, et al. Co-regulation of CYP3A4 and CYP3A5 and contribution to hepatic and intestinal midazolam metabolism. Mol Pharmacol. 2002;62(1):162–72.
Zhou HH, Adedoyin A, Wilkinson GR. Differences in plasma binding of drugs between Caucasians and Chinese subjects. Clin Pharmacol Ther. 1990;48(1):10–7.
Miao G, Yan Y, Chuanmin Z, Naiying L. Discussion on the relationship between normal hematocrit and geographical factors in China. Clin Hemorheol Microcirc. 1997;17(6):459–65.
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16(1):31–41.
Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med. 1999;130(6):461–70.
Hsiu K. Kidney size in normal Chinese adults: assessment by renosonogram and plain roentgenogram. Chang Gung Med J. 1983;6:93–9.
Hesse LM, Venkatakrishnan K, Court MH, von Moltke LL, Duan SX, Shader RI, et al. CYP2B6 mediates the in vitro hydroxylation of bupropion: potential drug interactions with other antidepressants. Drug Metab Dispos. 2000;28(10):1176–83.
Kirchheiner J, Klein C, Meineke I, Sasse J, Zanger UM, Murdter TE, et al. Bupropion and 4-OH-bupropion pharmacokinetics in relation to genetic polymorphisms in CYP2B6. Pharmacogenetics. 2003;13(10):619–26.
Romiti P, Giuliani L, Pacifici GM. Interindividual variability in the N-sulphation of desipramine in human liver and platelets. Br J Clin Pharmacol. 1992;33(1):17–23.
Senggunprai L, Yoshinari K, Yamazoe Y. Selective role of sulfotransferase 2A1 (SULT2A1) in the N-sulfoconjugation of quinolone drugs in humans. Drug Metab Dispos. 2009;37(8):1711–7.
Lin KM, Lau JK, Smith R, Phillips P, Antal E, Poland RE. Comparison of alprazolam plasma levels in normal Asian and Caucasian male volunteers. Psychopharmacology. 1988;96(3):365–9.
Fleishaker JC, Phillips JP, Eller MG, Smith RB. Pharmacokinetics and pharmacodynamics of alprazolam following single and multiple oral doses of a sustained-release formulation. J Clin Pharmacol. 1989;29(6):543–9.
Smith RB, Kroboth PD, Vanderlugt JT, Phillips JP, Juhl RP. Pharmacokinetics and pharmacodynamics of alprazolam after oral and IV administration. Psychopharmacology. 1984;84(4):452–6.
Bartoli A, Xiaodong S, Gatti G, Cipolla G, Marchiselli R, Perucca E. The influence of ethnic factors and gender on CYP1A2-mediated drug disposition: a comparative study in Caucasian and Chinese subjects using phenacetin as a marker substrate. Ther Drug Monit. 1996;18(5):586–91.
Loboz KK, Gross AS, Williams KM, Liauw WS, Day RO, Blievernicht JK, et al. Cytochrome P450 2B6 activity as measured by bupropion hydroxylation: effect of induction by rifampin and ethnicity. Clin Pharmacol Ther. 2006;80(1):75–84.
Chen K, Wang R, Wen SY, Li J, Wang SQ. Relationship of P450 2C9 genetic polymorphisms in Chinese and the pharmacokinetics of tolbutamide. J Clin Pharm Ther. 2005;30(3):241–9.
Madsen H, Enggaard TP, Hansen LL, Klitgaard NA, Brosen K. Fluvoxamine inhibits the CYP2C9 catalyzed biotransformation of tolbutamide. Clin Pharmacol Ther. 2001;69(1):41–7.
Hu XP, Xu JM, Hu YM, Mei Q, Xu XH. Effects of CYP2C19 genetic polymorphism on the pharmacokinetics and pharmacodynamics of omeprazole in Chinese people. J Clin Pharm Ther. 2007;32(5):517–24.
Andersson T, Holmberg J, Rohss K, Walan A. Pharmacokinetics and effect on caffeine metabolism of the proton pump inhibitors, omeprazole, lansoprazole, and pantoprazole. Br J Clin Pharmacol. 1998;45(4):369–75.
Rudorfer MV, Lane EA, Chang WH, Zhang MD, Potter WZ. Desipramine pharmacokinetics in Chinese and Caucasian volunteers. Br J Clin Pharmacol. 1984;17(4):433–40.
Yang G, Fu Z, Chen X, Yuan H, Yang H, Huang Y, et al. Effects of the CYP oxidoreductase Ala503Val polymorphism on CYP3A activity in vivo: a randomized, open-label, crossover study in healthy Chinese men. Clin Ther. 2011;33(12):2060–70.
Kharasch ED, Walker A, Hoffer C, Sheffels P. Intravenous and oral alfentanil as in vivo probes for hepatic and first-pass cytochrome P450 3A activity: noninvasive assessment by use of pupillary miosis. Clin Pharmacol Ther. 2004;76(5):452–66.
Kupferschmidt HH, Ha HR, Ziegler WH, Meier PJ, Krahenbuhl S. Interaction between grapefruit juice and midazolam in humans. Clin Pharmacol Ther. 1995;58(1):20–8.
Tsunoda SM, Velez RL, von Moltke LL, Greenblatt DJ. Differentiation of intestinal and hepatic cytochrome P450 3A activity with use of midazolam as an in vivo probe: effect of ketoconazole. Clin Pharmacol Ther. 1999;66(5):461–71.
Mandema JW, Tuk B, van Steveninck AL, Breimer DD, Cohen AF, Danhof M. Pharmacokinetic–pharmacodynamic modeling of the central nervous system effects of midazolam and its main metabolite alpha-hydroxymidazolam in healthy volunteers. Clin Pharmacol Ther. 1992;51(6):715–28.
Guo T, Mao GF, Xia DY, Su XY, Zhao LS. Pharmacokinetics of midazolam tablet in different Chinese ethnic groups. J Clin Pharm Ther. 2011;36(3):406–11.
Shih PS, Huang JD. Pharmacokinetics of midazolam and 1′-hydroxymidazolam in Chinese with different CYP3A5 genotypes. Drug Metab Dispos. 2002;30(12):1491–6.
Duan KM, Wang SY, Ouyang W, Mao YM, Yang LJ. Effect of quercetin on CYP3A activity in Chinese healthy participants. J Clin Pharmacol. 2012;52(6):940–6.
Backman JT, Kivisto KT, Olkkola KT, Neuvonen PJ. The area under the plasma concentration-time curve for oral midazolam is 400-fold larger during treatment with itraconazole than with rifampicin. Eur J Clin Pharmacol. 1998;54(1):53–8.
Fayer JL, Zannikos PN, Stevens JC, Luo Y, Sidhu R, Kirkesseli S. Lack of correlation between in vitro inhibition of CYP3A-mediated metabolism by a PPAR-gamma agonist and its effect on the clinical pharmacokinetics of midazolam, an in vivo probe of CYP3A activity. J Clin Pharmacol. 2001;41(3):305–16.
Olkkola KT, Backman JT, Neuvonen PJ. Midazolam should be avoided in patients receiving the systemic antimycotics ketoconazole or itraconazole. Clin Pharmacol Ther. 1994;55(5):481–5.
Gross AS, Bridge S, Shenfield GM. Pharmacokinetics of tolbutamide in ethnic Chinese. Br J Clin Pharmacol. 1999;47(2):151–6.
Caraco Y, Wilkinson GR, Wood AJ. Differences between white subjects and Chinese subjects in the in vivo inhibition of cytochrome P450s 2C19, 2D6, and 3A by omeprazole. Clin Pharmacol Ther. 1996;60(4):396–404.
Zhang A, Xing Q, Qin S, Du J, Wang L, Yu L, et al. Intra-ethnic differences in genetic variants of the UGT-glucuronosyltransferase 1A1 gene in Chinese populations. Pharmacogenomics J. 2007;7(5):333–8.
Ajir K, Smith M, Lin KM, Fleishaker JC, Chambers JH, Anderson D, et al. The pharmacokinetics and pharmacodynamics of adinazolam: multi-ethnic comparisons. Psychopharmacology. 1997;129(3):265–70.
Hendershot PE, Fleishaker JC, Lin KM, Nuccio ID, Poland RE. Pharmacokinetics of reboxetine in healthy volunteers with different ethnic descents. Psychopharmacology. 2001;155(2):148–53.
Yu KS, Cho JY, Shon JH, Bae KS, Yi SY, Lim HS, et al. Ethnic differences and relationships in the oral pharmacokinetics of nifedipine and erythromycin. Clin Pharmacol Ther. 2001;70(3):228–36.
Acknowledgments
We thank Pfizer Ltd (Sandwich, UK) for providing the demographic information on their cohort of healthy Chinese volunteers, and James Kay for his assistance with the preparation of this manuscript.
Conflicts of Interest
No sources of funding were used to conduct this study. Zoe E. Barter, Geoffrey T. Tucker and Karen Rowland-Yeo have no conflicts of interest that are directly relevant to the content of this study.
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Barter, Z.E., Tucker, G.T. & Rowland-Yeo, K. Differences in Cytochrome P450-Mediated Pharmacokinetics Between Chinese and Caucasian Populations Predicted by Mechanistic Physiologically Based Pharmacokinetic Modelling. Clin Pharmacokinet 52, 1085–1100 (2013). https://doi.org/10.1007/s40262-013-0089-y
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DOI: https://doi.org/10.1007/s40262-013-0089-y