Whole Body Pharmacokinetic Models

Abstract

The aim of the current review is to summarise the present status of physiologically based pharmacokinetic (PBPK) modelling and its applications in drug research, and thus serve as a reference point to people interested in the methodology. The review is structured into three major sections. The first discusses the existing methodologies and techniques of PBPK model development. The second describes some of the most interesting PBPK model implementations published. The final section is devoted to a discussion of the current limitations and the possible future developments of the PBPK modelling approach. The current review is focused on papers dealing with the pharmacokinetics and/or toxicokinetics of medicinal compounds; references discussing PBPK models of environmental compounds are mentioned only if they represent considerable methodological developments or reveal interesting interpretations and/or applications.The major conclusion of the review is that, despite its significant potential, PBPK modelling has not seen the development and implementation it deserves, especially in the drug discovery, research and development processes. The main reason for this is that the successful development and implementation of a PBPK model is seen to require the investment of significant experience, effort, time and resources. Yet, a substantial body of PBPK-related research has been accumulated that can facilitate the PBPK modelling and implementation process. What is probably lagging behind is the expertise component, where the demand for appropriately qualified staff far outreaches availability.

Simulation of Monoclonal Antibody Pharmacokinetics in HumansUsing a Minimal Physiologically Based Model

“…(1)(2)(3)(4)(5), assuming the absence of mAb. To define the initial conditions for a population of individuals the following approach was adopted.…”

“…Physiologically based pharmacokinetic (PBPK) models are being used increasingly to describe the disposition and interactions of small molecule drugs in different ethnic and disease populations (2). Similar approaches have also been used to develop PBPK models for protein therapeutics.…”

“…Their mouse model for IgG and its fragments (F(ab′) 2 and Fab′) included both diffusion and convection across the vascular membrane as well as convective flow into lymph. In 1994, Baxter and co-workers (4,5) published a mouse PBPK model and adapted the twopore model for transcapillary exchange, that had originally been proposed by Rippe and Haraldsson (6), to account for movement of IgG, F(ab) and F(ab′) 2 from the vascular to the interstitial space. This PBPK model also incorporated a tumor compartment to account for specific mAb binding to target.…”

Physiologically based pharmacokinetic modelling: a sub-compartmentalized model of tissue distribution

“…The aim is to analyze, interpret and predict the pharmacokinetics of drug candidates in the different stages of drug discovery and development (7,8). In toxicokinetics, physiologically based models are frequently used for the assessment of toxicological risks to humans (9)(10)(11).…”

“…More detailed and refined PBPK models are known, e.g., (7,8,11,18), but these models are either specifically designed for the compound of interest, or lack a generic parameterization in terms of readily available experimental data. In this article we present a sub-compartmentalized model of drug distribution in tissues, defined in terms of a system of differential equations.…”