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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

  • Guo Yu
  • Hong-Hao Zhou
  • Qing-Shan Zheng
  • Guo-Fu Li
Pharmacokinetics and Disposition
  • 49 Downloads

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.

Keywords

Interethnic scaling Fraction unbound Volume of distribution Healthy subjects Clinical pharmacokinetics 

Notes

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).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.National Institution of Drug Clinical TrialSubei People’s HospitalYangzhouChina
  2. 2.Department of Pharmacotherapy and Translational ResearchUniversity of FloridaGainesvilleUSA
  3. 3.Department of Clinical Pharmacology, Xiangya HospitalCentral South UniversityChangshaChina
  4. 4.Center for Drug Clinical ResearchShanghai University of Chinese MedicineShanghaiChina
  5. 5.Department of Pharmaceutics, College of PharmacyUniversity of FloridaGainesvilleUSA

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