Species Differences in Distribution and Prediction of HumanV_ssfrom Preclinical Data

Abstract

ABSTRACT:Prediction of human volume of distribution at steady state (V ss ) before first administration of a new drug candidate to humans has become an important part of the drug development process. This study examines the assumptions behind interspecies scaling techniques used to predict human V ss from preclinical data, namely the equivalency of V ss,u and/or f ut across species. In addition, several interspecies scaling techniques are evaluated side by side using a set of 67 reference compounds where observed V ss from rats, dogs, monkeys, and humans were compiled from the literature and where plasma protein binding was determined across species using an ultracentrifugation technique. Species similarity in V ss,u or f ut does not appear to be the norm among rats, dogs, monkeys, or humans. Despite this, interspecies scaling from rats, dogs, and monkeys is useful and can provide reasonably accurate predictions of human V ss , although some interspecies scaling approaches were better than others. For example, the performance of the common V ss,u or f ut equivalency approaches using average V ss,u or f ut across three preclinical species was superior to allometric scaling techniques. In addition, considering data from several preclinical species, using the equivalency approach, was superior to scaling from any single species. Although the mechanistic tissue composition equations available in the Simcyp populationbased pharmacokinetic simulator did not necessarily provide the most accurate predictions, and the equations used likely need refinement, they still provide the best opportunity for a mechanistic understanding and prediction of human V ss .

In Vitro–In Vivo Correlation for Low-Clearance Compounds Using Hepatocyte Relay Method

“…1, the rat, dog, and human hepatocyte relay method gave good prediction of in vivo intrinsic clearance [additional human data were collected during this study and added to the previously published set (Di et al, 2012)]. For most compounds, 9.0 6 3.9 1.2 Antipyrine 14 (Balani et al, 2002) 14 6 1.4 1.0 Naproxen 22 c (Suh et al, 1997) 20 6 3.0 1.1 (6)-Ketoprofen 48 -114 d (Granero and Amidon, 2008;Neirinckx et al, 2011) 24 6 1.2 2.0-4.7 e a F u and R b values were from the literature (Berry et al, 2011) or in-house data. b The equation CL iv = oral dose (Dose PO )/oral area under the curve (AUC PO ) Â F was used to derive i.v.…”

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

“…3) Does correction of plasma protein binding yield better or worse estimation of human VD? 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).…”

“…Prediction of human VD from in vitro tissue binding data has been reported over several years (Obach, 2007;Berry et al, 2011;Berezhkovskiy, 2012). The assumption is that in vitro surrogate measurements of tissue homogenate binding are representative of in vivo tissue binding.…”

“…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.…”

“…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? 2) Which species or species combination is the best approach?…”