Extrapolation of human pharmacokinetic parameters from rat, dog, and monkey data: Molecular properties associated with extrapolative success or failure

doi:10.1002/jps.20373

Journal of Pharmaceutical Sciences

Volume 94, Issue 7, July 2005, Pages 1467-1483

https://doi.org/10.1002/jps.20373 Get rights and content

Abstract

Human pharmacokinetic parameters are often predicted prior to clinical study from in vivo preclinical pharmacokinetic data. Recent data suggest that extrapolation of monkey pharmacokinetic data tends to be the most accurate method for predicting human clearance. In this study, the molecular features of a 103-compound dataset were analyzed to determine whether calculated physiochemical properties may be used to predict the extrapolative success or failure of rat, dog, and monkey data to project human pharmacokinetic parameters. Molecular properties (molecular weight, molar refractivity, log of the octanol–water partition coefficient, polar surface area, hydrogen bond donor/acceptor count, and rotatable bond count) were calculated, and relationships were sought for each preclinical species between extrapolative outcome for human clearance, distributional volume, and mean residence time, and each molecular feature or combination of features. The findings indicated that calculated molecular properties may be used both to predict extrapolative outcome for human pharmacokinetic properties from preclinical animal data, and to prospectively aid in the selection of an appropriate preclinical species in which to generate preclinical data to more reliably project human clearance. These observations demonstrate the utility of a combined computational and in vivo animal testing approach to projecting human pharmacokinetic parameters. © 2005 Wiley-Liss, Inc. and the American Pharmacists Association.

Section snippets

INTRODUCTION

The use of computational techniques to attempt to predict pharmacokinetic properties has become increasingly common in recent years.¹ Computational models that quantitatively predict properties such as oral bioavailability and plasma protein binding based solely on calculated physicochemical properties have been reported.2., 3., 4. Additionally, computational techniques have been used to highlight associations between calculated physicochemical properties and human pharmacokinetic properties,

Computation of Molecular Properties

The 103-compound data set of intravenous pharmacokinetic parameters from rat, dog, monkey, and human compiled from the literature by Ward and Smith⁷ was used for the present investigation; these data are summarized in Appendix I. Two-dimensional physicochemical and topological properties were computed for each of the compounds with in-house and commercial computational tools. Molecular weight was calculated as the mean natural isotope weight of the compound. Calculated logarithm of the

Molecular Properties

This data set consisted of a diverse and widely distributed range of values for each of the two-dimensional molecular properties calculated (Fig. 1). A strong correlation was observed between MW and CMR (r² = 0.955, data not shown); CMR, and not MW, was selected for subsequent analyses.

Clearance

As described by Ward and Smith,⁷ when considering CL qualitatively, monkey had a total of 75 of the 103 compounds (72.8%) that were extrapolative inliers, and rat and dog each had a total of 68 of 103 compounds

DISCUSSION

Over the past decade, a major emphasis in the area of pharmacokinetics has been the development of in silico or computational tools for the prediction of pharmacokinetic behavior on the basis of physicochemical properties.¹²^,¹³ The ultimate aim of such systems would be the accurate prediction of human dispositional properties before a new molecule is ever synthesized, much less tested in an in vitro or in vivo assay, however, this goal has not yet been attained. Additionally, it is likely that

Acknowledgements

The authors gratefully acknowledge Dr. Christopher Evans, Dr. Rakesh Nagilla, Theresa Roethke, and Leonard Azzarano for critical evaluation of this work.

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Citation Excerpt :
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Journal of Pharmaceutical Sciences

Abstract

Section snippets

INTRODUCTION

Computation of Molecular Properties

Molecular Properties

Clearance

DISCUSSION

Acknowledgements

REFERENCES (15)

Progress in predicting human ADME parameters in silico

J Pharmacol Toxicol Methods

Computational prediction of the plasma protein-binding percent of diverse pharmaceutical compounds

J Pharm Sci

Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings

Adv Drug Delivery Rev

A comprehensive analysis of the role of correction factors in the allometric predictivity of clearance from rat, dog, and monkey to human

J Pharm Sci

Prediction of pharmacokinetics prior to in vivo studies. 1. Mechanism-based prediction of volume of distribution

J Pharm Sci

Drug-like properties and the causes of poor solubility and poor permeability

J Pharmacol Toxicol Methods

Bioavailability prediction based on molecular structure for a diverse series of drugs

Pharm Res

Cited by (82)

Oral Cannabidiol does not alter Alcohol Seeking and Self‐Administration in Baboons

Nanoparticles that do not compete with endogenous ligands – Molecular characterization in vitro, acute safety in canine, and interspecies pharmacokinetics modeling to humans

In Silico Models of Human PK Parameters. Prediction of Volume of Distribution Using an Extensive Data Set and a Reduced Number of Parameters

Predicted values for human total clearance of a variety of typical compounds with differently humanized-liver mouse plasma data

Humans are animals, but are animals human enough? A systematic review and meta-analysis on interspecies differences in renal drug clearance

Development of a novel alcohol and nicotine concurrent access (ANCA) self-administration procedure in baboons

Research ArticlesExtrapolation of human pharmacokinetic parameters from rat, dog, and monkey data: Molecular properties associated with extrapolative success or failure

Abstract

Section snippets

INTRODUCTION

Computation of Molecular Properties

Molecular Properties

Clearance

DISCUSSION

Acknowledgements

J Pharmacol Toxicol Methods

J Pharm Sci

Adv Drug Delivery Rev

J Pharm Sci

J Pharm Sci

J Pharmacol Toxicol Methods

Bioavailability prediction based on molecular structure for a diverse series of drugs

Pharm Res

Research Articles
Extrapolation of human pharmacokinetic parameters from rat, dog, and monkey data: Molecular properties associated with extrapolative success or failure