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Xenobiotica
the fate of foreign compounds in biological systems
Volume 50, 2020 - Issue 3
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General Xenobiochemistry

Prediction of volume of distribution in humans: analysis of eight methods and their application in drug discovery

, , , &
Pages 270-279 | Received 24 Apr 2019, Accepted 26 May 2019, Published online: 19 Jun 2019
 

Abstract

  1. The performance of eight different methods to predict human volume of distribution (VDss) using a large data set (N > 100) was evaluated.

  2. The accuracy was assessed by the end points % within two-fold and absolute average fold error (AAFE). The ability to rank order was accessed by the σ and bias was examined using average fold error. Significance of observed differences was established using statistical permutation testing.

  3. The Rodgers-Lukova equation, a tissue composition model, for acids and single species scaling based on rat for other ion classes showed the best results in absence of non-rodent data.

  4. The semimechanistic Øie-Tozer model based on all thee preclinical species showed the best performance overall (81% within two-fold, AAFE 1.55, σ 0.62). This was not statistically significantly better at the 95% confidence level than the same model based on two preclinical species or single species scaling from monkey. Thus, the use of primates appears difficult to justify when the sole goal is to extrapolate human volume of distribution.

Disclosure statement

This work was supported by Merck. All authors were employed by Merck at the time this study was performed. The authors report no declarations of interest.

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