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

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.

A Perspective on the Prediction of Drug Pharmacokinetics and Disposition in Drug Research and Development

“…Overall, prediction of human VD ss from preclinical species is reliable and accurate. For most compounds, 70% to 80% of the predictions are within 2-to 3-fold of the measured human values (Lombardo et al, 2013b).…”

“…Many comprehensive reviews have been written on this topic (Obach, 2007;Berry et al, 2011;Zou et al, 2012;Lombardo et al, 2013b). Over 30 different in vivo, in vitro, and in silico methodologies are available to predict human VD.…”

“…Despite the empirical nature of interspecies scaling and the criticisms of this approach for predicting clearance and other PK parameters, it is quite effective in predicting human VD from in vivo animal data. Several methodologies are commonly used by DMPK scientists for interspecies scaling of VD (Lombardo et al, 2013b): 1) single species scaling, 2) allometric scaling with multiple species, 3) equivalency or proportionality approach, 4) Øie-Tozer model (Oie and Tozer, 1979), 5) Wajima method (Wajima et al, 2004), and 6) multiple linear regression approach. There are divergent points of view on interspecies scaling of human VD from preclinical animal data (Obach, 1997;Ward and Smith, 2004;Obach, 2007;Hosea et al, 2009;Sui et al, 2010;Berry et al, 2011;Jones et al, 2011b), raising the following questions: 1) Which method gives the most accurate prediction?…”

“…Depending on the animals used in the experiments, the diversity of the compounds, and the number of the compounds in the studies, the conclusions can be different (Obach, 1997;Ward and Smith, 2004;Obach, 2007;Hosea et al, 2009;Sui et al, 2010;Berry et al, 2011;Jones et al, 2011b). A recent study with a large set of well-characterized, structurally diverse compounds concluded that monkey was superior to dog or/and rat in all the methods tested, presumably because monkey is evolutionarily closest to human (Lombardo et al, 2013b). Both uptake and efflux transporters in monkey have been shown to be more predictive of human than rodents and dogs (Syvänen et al, 2009;Shen et al, 2013).…”

Physiologically Based Pharmacokinetic (PBPK) Modeling and Simulation Approaches: A Systematic Review of Published Models, Applications, and Model Verification

“…Various allometric scaling, in vitro-to-in vivo extrapolation (IVIVE), and in silico methods have been developed over the years to enable predictions of human pharmacokinetics prior to first in human dosing. More than 30 different methods exist to predict human volume of distribution (Di et al, 2013), including interspecies scaling (Lombardo et al, 2013a) and in silico methods. Generally, in vivo animal data, log P values, plasma protein binding, and blood-to-plasma ratios are used to predict the human steady-state volume of distribution and tissue-to-plasma partitioning (Poulin andTheil, 2000, 2002;Poulin et al, 2001;Berezhkovskiy, 2004;Rodgers et al, 2005;Rodgers and Rowland, 2006).…”