Prediction of human clearance (CL) and volume of distribution (VD)

doi:10.1016/j.ddtec.2004.10.007

Drug Discovery Today: Technologies

Volume 1, Issue 4, December 2004, Pages 389-395

https://doi.org/10.1016/j.ddtec.2004.10.007 Get rights and content

The crucial pharmacokinetic parameters ‘volume of distribution’ and ‘human clearance’ determine the extent and duration a compound remains in an organism. Potential drug candidates will fail to become successful drugs on the market without favorable values for these parameters, even if they are most efficacious at the target in vitro.

The prediction of volume of distribution and human clearance in drug research and development is a key technology to assess possible drug candidates.

Section Editors:

Han van de Waterbeemd, Christopher Kohl – Pfizer Global Research & Development, Sandwich Laboratories, PDM (Pharmacokinetics, Dynamics and Metabolism), ipc 664, Ramsgate Road, Sandwich, Kent, UK CT13 9NJ

The prediction of the fundamental pharmacokinetic parameters clearance and volume of distribution is essential to rational compound progression in the drug discovery phase. Improvements in the accuracy and reliability of these predictions could considerable improve the chances of success in drug development in many pharmaceutical companies. Jörg Keldenich has many years of industrial experience in the modeling and prediction of ADME properties. He reviews general approaches and recent advances in the prediction of human clearance and volume from early discovery to the preclinical phase.

Introduction

With the rising costs incurred in developing a chemical entity to a drug on the market, the requirements for potential drug candidates have been increased and will augment further. Therefore, there is no choice but to increase the efficiency and the ability to pick the molecule that has the best potential to succeed in overcoming the hurdles of drug development.

To assess such potential in a molecule, reliable prediction methods for essential characteristics (e.g. pharmacokinetic properties) of the future drug are necessary and have to be used not only by pharmacokinetic experts but also by medicinal chemists. Thus, structure property relations (spr) (see Glossary) on these parameters help to synthesize molecules with favorable pharmacokinetic properties.

Properties, such as volume of distribution (vd) and human clearance (cl) (see Glossary), are key parameters in pharmacokinetics and are influenced by several different properties (Fig. 1).

Section snippets

Five key technologies

Three technologies are able to predict these parameters with high accuracy:

•
Allometric species scaling.
•
Direct scaling from human tissue in vitro.
•
Scaling from animal and human tissue in vitro combined with species scaling.

These standard methods are widely used in the pharmaceutical industry and will be described briefly. The reader is referred to excellent review articles 1, 2, 3.

The remaining technologies are developed to establish SPRs that guide chemical synthesis during research and

Allometric species scaling

A relationship between anatomy and physiological function is assumed for this scaling. In its simplest form, the parameter of interest (X) measured in different species is correlated with their body weights (W). The correlation function is mostly expressed as a power function: $X = a {(W)}^{b}$

By extrapolation, the human parameter is calculated using the body weight of a standardized human creature (70 kg).

Other anatomical parameters, such as body surface area, brain weight or maximum life span potential,

Direct scaling from human tissue in vitro

With the recent progress of in vitro tools, especially for the determination of metabolic intrinsic clearance from human liver tissues (microsomes or hepatocytes), the direct scaling from in vitro to in vivo attracts more and more attention.

This approach converts the intrinsic clearance measured in the in vitro incubation into one for the liver, followed by the use of a liver model transforming in vitro into in vivo hepatic clearance (for liver models see Section: Mechanistic models and in

Scaling from animal and human tissue in vitro combined with species scaling

When human material is not available in a sufficient amount, tissues from preclinical species can be used to perform in vitro measurements. Additionally, a general correlation of these parameters measured in animal tissues to those measured in humans is needed, which is possible via species scaling.

This approach tries to minimize possible errors in pure allometric or pure in vitro direct scaling [10]. For instance, it uses the in vivo clearance in one preclinical species and the in vitro

Mechanistic models and in silico approaches to predict VD

In addition to the approaches mentioned above, further models that are based on measured properties use physicochemical data as input and make use of mechanistical models to predict VD. The three models that have been reported differ from each other.

Model 1 11, 12 rearranges the definition of VD to calculate the unbound fraction in whole body tissue from VD values in humans of known drugs. Correlating this parameter to measured values of log D and pK_a (see Glossary) yields equations that,

Mechanistic models and in silico approaches to predict CL

Clearance is a more complex parameter than VD because specific processes are responsible for the elimination of drugs from the body. Metabolism and/or excretion of the drug is because of specific reactions of enzymes and transporters with the drug molecule. In addition, evidence that permeation into liver cells is not always passively driven is increasing.

The current models used for liver to scale measured clearance rates in vitro to the total body clearance are based on the following

Concluding remarks

The approaches discussed in this review (Table 1) are meant to be used for different purposes. A possible modeling strategy is shown in Fig. 2.

Computational models are adequate for early research and large numbers of compounds or prediction before synthesis. By contrast, species scaling, direct scaling and the combination of both are useful for precise predictions during preclinical development. The in vitro methods are located in between these poles. Some can be done in high-throughput mode,

Birkett, D.J. (2000) Pharmacokinetics Made Easy (1st edn), McGraw Hill
Wilkinson, G.R. and Shand, D.G. (1975) A physiological approach to hepatic drug clearance. Clin. Pharmacol. Ther. 18, 377–390
Mahmood, I. (2002) Prediction of clearance in humans from in vitro human liver microsomes and allometric scaling. A comparative study of the two approaches. Drug Metabol. Drug Interact. 1949–1964
Lavé, T. et al. (1999) Prediction of hepatic metabolic clearance based on interspecies allometric scaling

Outstanding issues

•
Refine models on CL and VD to include active transport, permeation and intracellular tissue binding to improve understanding of the overall process and the scaling to humans, especially for those compounds where the current models fail.
•
Publish more cases about failed predictions to improve knowledge about the overall process and to identify potential model compounds where deeper investigations can be conducted.
•
Refine and broaden in silico models towards increased structural diversity. Consider

Glossary

CL: clearance is a measure of the efficiency by which a drug is eliminated from the body. It is defined as the volume of blood cleared of drug per unit time. Clearance is because of distinct pathways in specific organs. The major contributing organs are liver and kidney.
Lipophilicity: this property describes the distribution of a compound between a lipid-like phase and water. This lipid-like phase consists of octanol, olive oil, liquid chromatography phases or model lipids (e.g. egg-lecithin),

References (27)

P. Poulin et al.
Prediction of pharmacokinetics prior to in vivo studies. 1. Mechanism-based prediction of volume of distribution
J. Pharm. Sci.
(2002)
S. Willmann
PK-Sim^®: a physiologically based pharmacokinetic “whole-body” model
Biosilico
(2003)
F-P. Theil
Utility of physiologically based pharmacokinetic models to drug development and rational drug discovery candidate selection
Toxicol. Lett.
(2003)
J. Langowski et al.
Computer systems for the prediction of xenobiotic metabolism
Adv. Drug Deliv. Rev.
(2002)
I. Mahmood et al.
Interspecies scaling: predicting clearance of drugs in humans. Three different approaches
Xenobiotica
(1996)
T. Lavé
Interspecies scaling
Lavé, T. et al. (2002) Prediction of human pharmacokinetics based on preclinical in vitro and in vivo data. In...
J.R. Banavar
Size and form in efficient transportation networks
Nature
(1999)
J.R. Banavar
River, blood and transportation networks
Nature
(2000)
V. Karalis et al.
Drug disposition viewed in terms of the fractal volume of distribution
Pharm. Res.
(2002)

I. Mahmood

Interspecies scaling: predicting oral clearance in humans

Am. J. Ther.

(2002)

S. Björkman

Prediction of volume of distribution of a drug: which tissue-plasma partition coefficients are needed?

J. Pharm. Pharmacol.

(2002)

J.T. MacGregor

In vitro human tissue models in risk assessment: report of a consensus-building workshop

Toxicol. Sci.

(2001)

Cited by (11)

Prediction of volume of distribution values in human using immobilized artificial membrane partitioning coefficients, the fraction of compound ionized and plasma protein binding data
2009, European Journal of Medicinal Chemistry
Citation Excerpt :
Various methods have been proposed to characterize VD including (i) the extrapolation of animal data [3–8], (ii) physiologically based pharmacokinetic (PBPK) model [6,9–13] and (iii) computational (in silico) approaches [14–20], Additionally, two biomimetic-binding measurement, the phospholipids binding (immobilized artificial membrane IAM) and the plasma protein binding (human serum albumin HSA) have been used to model VD in human [21]. These methods have been discussed in detail in several review papers [22–25]. In brief, interspecies scaling could serve as a guideline for better planning of clinical studies; nevertheless, animal experiments are needed, so, labor, time, resources and even ethical considerations are involved in drug research and development processes.
We developed an improved Lombardeo's method (J. Med. Chem., 2004) for prediction of VD_ss in human. With Elog D substituted by log k_IAM, together with f_{i (7.4)} (the fraction of compound ionized at pH 7.4) and log f_u (logarithmic fraction of compound unbound in plasma), the predictive equation of f_ut (the fraction of the compound unbound in tissues) for the 121 compounds was built, predictive VD_ss was further obtained from the Øie–Tozer equation. Our model could be applicable to structurally diverse compounds, including acids, bases, neutrals, and ampholytes. Interior and exterior validation results indicated the model had a robust predictive ability. Compared to the Lombardeo's and Hollósy's (J. Med. Chem., 2006) methods, our model can be generally applicable with better predictive accuracy.
Properties and in silico ADME modeling in drug discovery
2013, Medicinal Chemistry
The utility of pharmacokineticpharmacodynamic modeling in the discovery and optimization of selective S1P1 agonists
2012, Xenobiotica
Using expression data for quantification of active processes in physiologically based pharmacokinetic modeling
2012, Drug Metabolism and Disposition
Comparative evaluation of US food and drug administration and pharmacologically guided approaches to determine the maximum recommended starting dose for first-in-human clinical trials in adult healthy men
2011, Journal of Clinical Pharmacology
Contribution of molecular properties to extrapolation of the volume of distribution in human from preclinical animal species data
2010, Biopharmaceutics and Drug Disposition

View all citing articles on Scopus

View full text

Drug developmentPrediction of human clearance (CL) and volume of distribution (VD)

Section Editors:

Introduction

Section snippets

Five key technologies

Allometric species scaling

Direct scaling from human tissue in vitro

Scaling from animal and human tissue in vitro combined with species scaling

Mechanistic models and in silico approaches to predict VD

Mechanistic models and in silico approaches to predict CL

Concluding remarks

Related articles

Links

Outstanding issues

Glossary

J. Pharm. Sci.

Biosilico

Toxicol. Lett.

Adv. Drug Deliv. Rev.

Interspecies scaling: predicting clearance of drugs in humans. Three different approaches

Xenobiotica

Interspecies scaling

Size and form in efficient transportation networks

Nature

River, blood and transportation networks