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

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

Results

The interethnic extrapolation approach of f_u provided a high accuracy with 94.7% scaled Chinese f_u values (n = 19) being within a 1.25%-fold error range. Specifically, 100% of scaled Chinese f_u 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 f_u values were ≤ 30%, with a majority of those ≤ 20%. Additionally, correlation between the prediction errors and the observed f_u levels was not observed. Regarding interethnic scaling of V_d, the bodyweight-normalized V_d,u instead of V_d was similar across ethnic groups.

Conclusion

The current study verified for the first time the ability to scale Chinese f_u from Caucasian values after examining with experimentally determined f_u values of a variety of reference compounds. Similarities in bodyweight-normalized V_d,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 f_u and V_d from healthy non-obese Caucasian to Chinese subjects.

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