Comprehensive Assessment of Human Pharmacokinetic Prediction Based on In Vivo Animal Pharmacokinetic Data, Part 1: Volume of Distribution at Steady State

TLDR

The study evaluates how well human volume of distribution at steady state can be predicted from rat, dog, and monkey data for nearly 400 compounds. The authors compiled the largest publicly available dataset, augmenting literature values with in‑house plasma protein binding measurements. Analysis shows that dog‑plus‑monkey data in the iie‑Tozer equation yields the highest prediction success, while using fraction unbound in plasma generally reduces accuracy; dog‑only or dog‑plus‑rat approaches remain reasonable alternatives.

Abstract

The authors present a comprehensive analysis on the estimation of volume of distribution at steady state (VD(ss) ) in human based on rat, dog, and monkey data on nearly 400 compounds for which there are also associated human data. This data set, to the authors- knowledge, is the largest publicly available, has been carefully compiled from literature reports, and was expanded with some in-house determinations such as plasma protein binding data. This work offers a good statistical basis for the evaluation of applicable prediction methods, their accuracy, and some methods-dependent diagnostic tools. The authors also grouped the compounds according to their charge classes and show the applicability of each method considered to each class, offering further insight into the probability of a successful prediction. Furthermore, they found that the use of fraction unbound in plasma, to obtain unbound volume of distribution, is generally detrimental to accuracy of several methods, and they discuss possible reasons. Overall, the approach using dog and monkey data in the íie-Tozer equation offers the highest probability of success, with an intrinsic diagnostic tool based on aberrant values (<0 or >1) for the calculated fraction unbound in tissue. Alternatively, methods based on dog data (single-species scaling) and rat and dog data (íie-Tozer equation with 2 species or multiple regression methods) may be considered reasonable approaches while not requiring data in nonhuman primates.