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

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

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

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