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Interethnic scaling of fraction unbound of a drug in plasma and volume of distribution: an analysis of extrapolation from Caucasians to Chinese

  • Pharmacokinetics and Disposition
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

Prospective prediction of pharmacokinetic properties for individuals of different ethnic groups could provide useful information for the design of multiregional clinical trials. The accuracy of interethnic scaling of fraction unbound (fu) of a drug could determine in large part the predictive capability of volume of distribution as well as renal clearance. As such, exploring the interethnic extrapolation of fu from healthy Caucasian to Chinese subjects and associated effect on the scaling of volume of distribution is highly warranted.

Methods

This study assessed the interethnic scaling of fu from healthy Caucasians to Chinese by using physiologically based principles and verified the approach after examining with experimentally determined fu values of a variety of reference compounds with differing binding characteristics. Moreover, the fundamental assumption of interethnic extrapolation of volume of distribution (Vd), namely the equivalency of unbound Vd (Vd,u) across different ethnic groups, was tested on the basis of observed Vd data derived from comprehensive literature analysis and scaled fu values through qualified extrapolation method.

Results

The interethnic extrapolation approach of fu provided a high accuracy with 94.7% scaled Chinese fu values (n = 19) being within a 1.25%-fold error range. Specifically, 100% of scaled Chinese fu values for the albumin-bound compounds and 90% for those bound to alpha 1-acid glycoprotein fell within the 1.25%-fold error range. All the percentage prediction errors of scaled Chinese fu values were ≤ 30%, with a majority of those ≤ 20%. Additionally, correlation between the prediction errors and the observed fu levels was not observed. Regarding interethnic scaling of Vd, the bodyweight-normalized Vd,u instead of Vd was similar across ethnic groups.

Conclusion

The current study verified for the first time the ability to scale Chinese fu from Caucasian values after examining with experimentally determined fu values of a variety of reference compounds. Similarities in bodyweight-normalized Vd,u between non-obese Caucasians and Chinese have also been shown for the first time. This investigation could greatly enhance the confidence in the interethnic extrapolation of fu and Vd from healthy non-obese Caucasian to Chinese subjects.

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References

  1. Heuberger J, Schmidt S, Derendorf H (2013) When is protein binding important? J Pharm Sci 102(9):3458–3467

    Article  CAS  PubMed  Google Scholar 

  2. Zhou HH, Koshakji RP, Silberstein DJ, Wilkinson GR, Wood AJ (1989) Racial differences in drug response. Altered sensitivity to and clearance of propranolol in men of Chinese descent as compared with American whites. N Engl J Med 320(9):565–570

    Article  CAS  PubMed  Google Scholar 

  3. Zhou HH, Wood AJ (1990) Differences in stereoselective disposition of propranolol do not explain sensitivity differences between white and Chinese subjects: correlation between the clearance of (−)- and (+)-propranolol. Clin Pharmacol Ther 47(6):719–723

    Article  CAS  PubMed  Google Scholar 

  4. Shu Y, Cheng ZN, Liu ZQ, Wang LS, Zhu B, Huang SL, Ou-Yang DS, Zhou HH (2001) Interindividual variations in levels and activities of cytochrome P-450 in liver microsomes of Chinese subjects. Acta Pharmacol Sin 22(3):283–288

    CAS  PubMed  Google Scholar 

  5. Li GF, Yu G, Liu HX, Zheng QS (2014) Ethnic-specific in vitro–in vivo extrapolation and physiologically based pharmacokinetic approaches to predict cytochrome P450-mediated pharmacokinetics in the Chinese population: opportunities and challenges. Clin Pharmacokinet 53(2):197–202

    Article  PubMed  Google Scholar 

  6. Kim K, Johnson JA, Derendorf H (2004) Differences in drug pharmacokinetics between East Asians and Caucasians and the role of genetic polymorphisms. J Clin Pharmacol 44(10):1083–1105

    Article  CAS  PubMed  Google Scholar 

  7. Bajaj G, Gupta M, Heidi Wang HG, Barrett JS, Tan M, Rupalla K, Bertz R, Sheng J (2018) Challenges and opportunities with oncology drug development in China. Clin Pharmacol Ther. https://doi.org/10.1002/cpt.1017

  8. Toutain PL, Bousquet-Melou A (2002) Free drug fraction vs free drug concentration: a matter of frequent confusion. J Vet Pharmacol Ther 25(6):460–463

    Article  CAS  PubMed  Google Scholar 

  9. Deitchman AN, Singh RSP, Derendorf H (2018) Nonlinear protein binding: not what you think. J Pharm Sci 107(7):1754–1760

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Zhou HH, Adedoyin A, Wilkinson GR (1990) Differences in plasma binding of drugs between Caucasians and Chinese subjects. Clin Pharmacol Ther 48(1):10–17

    Article  CAS  PubMed  Google Scholar 

  11. Rudorfer MV, Lane EA, Chang WH, Zhang MD, Potter WZ (1984) Desipramine pharmacokinetics in Chinese and Caucasian volunteers. Br J Clin Pharmacol 17(4):433–440

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Ghoneim MM, Korttila K, Chiang CK, Jacobs L, Schoenwald RD, Mewaldt SP, Kayaba KO (1981) Diazepam effects and kinetics in Caucasians and Orientals. Clin Pharmacol Ther 29(6):749–756

    Article  CAS  PubMed  Google Scholar 

  13. Spector R, Choudhury AK, Chiang CK, Goldberg MJ, Ghoneim MM (1980) Diphenhydramine in Orientals and Caucasians. Clin Pharmacol Ther 28(2):229–234

    Article  CAS  PubMed  Google Scholar 

  14. Goldberg MJ, Spector R, Johnson GF (1982) Racial background and lidocaine pharmacokinetics. J Clin Pharmacol 22(8–9):391–394

    Article  CAS  PubMed  Google Scholar 

  15. Feely J, Grimm T (1991) A comparison of drug protein binding and alpha 1-acid glycoprotein concentration in Chinese and Caucasians. Br J Clin Pharmacol 31(5):551–552

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Cheng YF, Jiang J, Hu P, Reinholdsson I, Guo W, Åsenblad N, Nilsson D (2008) Pharmacokinetics of 8-hour intravenous infusion of NXY-059: a phase I, randomized, double-blind (within dose panels), placebo-controlled study in healthy Chinese volunteers. Clin Ther 30(12):2342–2353

    Article  CAS  PubMed  Google Scholar 

  17. Anderson PJ, Critchley JA, Tomlinson B, Resplandy G (1995) Comparison of the pharmacokinetics and pharmacodynamics of oral doses of perindopril in normotensive Chinese and Caucasian volunteers. Br J Clin Pharmacol 39(4):361–368

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Wong YC, Chan K, Lau OW, Aun C, Houghton IT (1991) Protein binding characterization of pethidine and norpethidine and lack of interethnic variability. Methods Find Exp Clin Pharmacol 13(4):273–279

    CAS  PubMed  Google Scholar 

  19. Wanwimolruk S, Denton JR (1992) Plasma protein binding of quinine: binding to human serum albumin, alpha 1-acid glycoprotein and plasma from patients with malaria. J Pharm Pharmacol 44(10):806–811

    Article  CAS  PubMed  Google Scholar 

  20. Hendershot PE, Fleishaker JC, Lin KM, Nuccio ID, Poland RE (2001) Pharmacokinetics of reboxetine in healthy volunteers with different ethnic descents. Psychopharmacology 155(2):148–153

    Article  CAS  PubMed  Google Scholar 

  21. US Food and Drug Administration (FDA). Drugs@FDA database: the FDA approved drug products. Available at: https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm. Accessed 15 April 2017

  22. Guang W, Baraldo M, Furlanut M (1995) Calculating percentage prediction error: a user’s note. Pharmacol Res 32(4):241–248

    Article  Google Scholar 

  23. Poulin P, Theil FP (2009) Development of a novel method for predicting human volume of distribution at steady-state of basic drugs and comparative assessment with existing methods. J Pharm Sci 98(12):4941–4961

    Article  CAS  PubMed  Google Scholar 

  24. Poulin P (2015) Drug distribution to human tissues: prediction and examination of the basic assumption in in vivo pharmacokinetics-pharmacodynamics (PK/PD) research. J Pharm Sci 104(6):2110–2118

    Article  CAS  PubMed  Google Scholar 

  25. Allen A, Bal J, Cheesbrough A, Hamilton M, Kempsford R (2014) Pharmacokinetics and pharmacodynamics of intravenous and inhaled fluticasone furoate in healthy Caucasian and East Asian subjects. Br J Clin Pharmacol 77(5):808–820

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Lin KM, Lau JK, Smith R, Phillips P, Antal E, Poland RE (1988) Comparison of alprazolam plasma levels in normal Asian and Caucasian male volunteers. Psychopharmacology 96(3):365–369

    Article  CAS  PubMed  Google Scholar 

  27. Yang L, Sunzel M, Xu P, Edeki T, Wilson D, Li J, Li H (2015) Evaluation of the pharmacokinetics and safety of single and multiple ceftaroline fosamil infusions in healthy Chinese and Western subjects. Int J Clin Pharmacol Ther 53(8):681–691

    Article  PubMed  Google Scholar 

  28. Aiudi A, Miller B, Krishna G, Adedoyin A, Xiao A (2016) Pharmacokinetics, safety, and tolerability of ceftolozane/tazobactam in healthy Japanese, Chinese, and white subjects. Fundam Clin Pharmacol 30(6):625–633

    Article  CAS  PubMed  Google Scholar 

  29. Jönsson A, Chan JC, Rydberg T, Vaaler S, Hallengren B, Cockram CS, Critchley JA, Melander A (2000) Pharmacodynamics and pharmacokinetics of intravenous glibenclamide in Caucasian and Chinese patients with type-2 diabetes. Eur J Clin Pharmacol 55(10):721–727

    Article  PubMed  Google Scholar 

  30. Xu J, Li Y, Sun X, Zhang D, Liu R, Ziti-Ljajic S, Shi D, Xue F, le bail N, Xu R (2017) A phase I and pharmacokinetic study of afilbercept with FOLFIRI: comparison of Chinese and Caucasian populations. Investig New Drugs 35(4):463–470

    Article  CAS  Google Scholar 

  31. Mahmood I (2012) Prediction of clearance and volume of distribution in the obese from normal weight subjects: an allometric approach. Clin Pharmacokinet 51(8):527–542

    Article  CAS  PubMed  Google Scholar 

  32. Yasuda SU, Zhang L, Huang SM (2008) The role of ethnicity in variability in response to drugs: focus on clinical pharmacology studies. Clin Pharmacol Ther 84(3):417–423

    Article  PubMed  Google Scholar 

  33. Lin JH (1995) Species similarities and differences in pharmacokinetics. Drug Metab Dispos 23(10):1008–1021

    CAS  PubMed  Google Scholar 

  34. Berry LM, Li C, Zhao Z (2011) Species differences in distribution and prediction of human Vss from preclinical data. Drug Metab Dispos 39(11):2103–2116

    Article  CAS  PubMed  Google Scholar 

  35. Sawada Y, Hanano M, Sugiyama Y, Harashima H, Iga T (1984) Prediction of the volumes of distribution of basic drugs in humans based on data from animals. J Pharmacokinet Biopharm 12(6):587–596

    Article  CAS  PubMed  Google Scholar 

  36. Yu G, Zheng QS, Li GF (2014) Similarities and differences in gastrointestinal physiology between neonates and adults: a physiologically based pharmacokinetic modeling perspective. AAPS J 16(6):1162–1166

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Li GF, Zheng QS, Yu Y, Zhong W, Zhou HH, Qiu F, Wang G, Yu G, Derendorf H (2019) Impact of ethnicity-specific hepatic microsomal scaling factor, liver weight, and CYP1A2 content on physiologically-based prediction of CYP1A2-mediated pharmacokinetics in young and elderly Chinese adults. Clin Pharmacokinet (Accept)

  38. Li GF, Wang K, Chen R, Zhao HR, Yang J, Zheng QS (2012) Simulation of the pharmacokinetics of bisoprolol in healthy adults and patients with impaired renal function using whole-body physiologically based pharmacokinetic modeling. Acta Pharmacol Sin 33(11):1359–1371

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Grover A, Benet LZ (2009) Effects of drug transporters on volume of distribution. AAPS J 11(2):250–261

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Li GF, Yu G, Li Y, Zheng Y, Zheng QS, Derendorf H (2018) Quantitative estimation of plasma free drug fraction in patients with varying degrees of hepatic impairment: a methodological evaluation. J Pharm Sci 107(7):1948–1956​

  41. Li GF, Zheng QS (2018) Modeling drug disposition and drug–drug interactions through hypothesis-driven physiologically based pharmacokinetics: a reversal translation perspective. Eur J Drug Metab Pharmacokinet 43(3):369–371

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors thank Dr. Yichao Yu (Department of Pharmaceutics, University of Florida) for calculating ceftaroline Vss values facilitating this analysis. The authors thank anonymous reviewers for their constructive comments and scientific input, which help us to improve the quality of manuscript significantly.

Funding

This work was financially supported in part by the National Natural Science Foundation of China (No. 81603209).

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Authors and Affiliations

  1. National Institution of Drug Clinical Trial, Subei People’s Hospital, Yangzhou, Jiangsu, China

    Guo Yu & Guo-Fu Li

  2. Department of Pharmacotherapy and Translational Research, University of Florida, Gainesville, FL, 32610, USA

    Guo Yu

  3. Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, Hunan, China

    Guo Yu & Hong-Hao Zhou

  4. Center for Drug Clinical Research, Shanghai University of Chinese Medicine, Shanghai, China

    Qing-Shan Zheng & Guo-Fu Li

  5. Department of Pharmaceutics, College of Pharmacy, University of Florida, 1345 Center Drive, P3-06, Gainesville, FL, 32610-0494, USA

    Guo-Fu Li

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  1. Guo Yu
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Yu, G., Zhou, HH., Zheng, QS. et al. Interethnic scaling of fraction unbound of a drug in plasma and volume of distribution: an analysis of extrapolation from Caucasians to Chinese. Eur J Clin Pharmacol 75, 543–551 (2019). https://doi.org/10.1007/s00228-018-02610-z

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  • DOI: https://doi.org/10.1007/s00228-018-02610-z

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