MEGen: A Physiologically Based Pharmacokinetic Model Generator

Abstract

Physiologically based pharmacokinetic models are being used in an increasing number of different areas. However, they are perceived as complex, data hungry, resource intensive, and time consuming. In addition, model validation and verification are hindered by the relative complexity of the equations. To begin to address these issues a web application called MEGen for the rapid construction and documentation of bespoke deterministic PBPK model code is under development. MEGen comprises a parameter database and a model code generator that produces code for use in several commercial software packages and one that is freely available. Here we present an overview of the current capabilities of MEGen, and discuss future developments.

Keywords: database; equation; generator; pharmacokinetic; physiologically based.

Figure 1

MEGen components and outputs.

Figure 2

Database search page showing details of a selected parameter.

Figure 3

Database search page: application of filters.

Figure 4

Initial configuration page.

Figure 5

Configuration pages: selection of, (A) animal, (B) chemical, and (C) compartments.

Figure 6

Configuration page: selection of optional parts of model.

Figure 7

Parameter selection using the Caddy.

Figure 8

Auto-population of model using the Caddy editor.

Figure 9

Model review page.

Figure 10

Generate code page.

Figure 11

A conceptual view of the data schema showing the hierarchical arrangement of parameter groupings.

Figure 12

Mass-balance check functions: quotient, dose against mass, and mass/dose quotient against time plot for the vinyl chloride model exported and visualized in acslX Libero.

Figure 13

Reproduction of Figure 2A from Himmelstein et al. (2004). In vivo closed-chamber gas uptake of β-chloroprene in the B6C3F1 mouse. Mean experimental data (symbols) and simulations (lines) represent initial concentrations of 2, 10, 50 270, or 363 ppm. PBPK model exported in Berkeley Madonna syntax.

Figure 14

Reproduction of Figure 5 from Clewell et al. (2001). Simulations (lines) and experimentally determined (symbols) glutathione concentrations (as percent of control animal levels) at 0, 20, and 44 h following 4-h inhalation exposures to VC at 5760, 192, 57.6, 19.2, and 5.76 ppm. PBPK model exported in acslX Libero version 3.0.1.6.

Figure 15

Reproduction of Figure 5 from Loizou and Spendiff (2004). Simulated (line) versus measured (symbols) blood ethanol concentrations following intra-venous administration of 0.4 g kg⁻¹ ethanol for 1 h. PBPK model exported in MATLAB version R2010b.