Bayer PK-Sim

Category Cross-Omics>Agent-Based Modeling/Simulation/Tools

Abstract PK-Sim® is a unique software tool for the summary and evaluation of pre-clinical and clinical experimental results on absorption, distribution, metabolism and excretion (ADME) by means of whole-body physiologically-based pharmacokinetic (PBPK) modeling and simulation.

It allows the straight forward construction of highly specific physiologically-based pharmacokinetic (PK) models by the incorporation of in-vitro and in-vivo experimental data gathered in pre- clinical and clinical phases and, thereby, to develop a consistent mechanistic understanding of the key processes driving pharmacokinetics.

The resulting PK model allows you to extrapolate various scenarios such as, e.g. new application routes or schemes, new formulations, special populations, etc. and, thereby, to support the preparation of the study design of succeeding pre-clinical and clinical experiments.

This new quality of mechanistic understanding of pharmacokinetics can serve as an additional input for competent go/no-go decision making.

PK-Sim simulates the processes responsible for absorption, distribution, metabolism and excretion (ADME) of active compounds in the body.

The features/capabilities of the PK-Sim Clinical full version containing all available Add-on modules (see below...) include:

1) Simulation of mammalian pharmacokinetics following single or multiple intravenous or oral administrations in various species (e.g. mouse, rat, dog, monkey, human);

2) Full control over physiological properties: organ volumes and blood flow rates are pre-defined and can easily be adjusted;

3) Minimized requirements for compound specific input data: lipophilicity, plasma protein binding, molecular weight, solubility, pKa- value(s), hepatic and renal clearances;

4) Generation of pH versus solubility tables;

5) Simulation of the dissolution dynamic of a solid particle formulation with predefined particle size distribution;

6) Physiology-based simulation of gastro-intestinal transit and absorption;

7) Simulation of saturable active uptake and efflux processes as well as luminal degradation and gut wall metabolism;

8) Permeation limited distribution model;

9) Population database providing physiological information that mainly depends on age, gender and BMI for different races;

10) Species database providing physiological data for different animal models;

11) Definition of trial populations by age, gender and body size;

12) Scaling of anatomical parameters to body size;

13) Random inter-individual variability predefined or user defined;

14) Minimum, mean and maximum concentration curves, concentration density plots;

15) Median and percentile curves;

16) Statistics of pharmacokinetic parameters;

17) Distribution plots for pharmacokinetic parameters;

18) Output of concentration-time curves and pharmacokinetic parameters (fraction absorbed, AUC, Vss) in each body organ (whole organ, interstitial, or intracellular concentration, total and unbound concentration);

19) Databases for compound data (project specific and global);

20) Project database for convenient management of simulation settings and results;

21) Import/Export functions for experimental and simulation data;

22) Convenient and intuitive graphical user interface (GUI); and

23) Advanced graphical output of simulation results.

PK-Sim Add-on modules -- Depending on the package purchased these modules are either integrated or can be upgraded at any time.

Species Modules -- PK-Sim® can simulate the pharmacokinetics in five (5) different species (mice, rats, dogs, monkeys and humans). Availability of the species depends on the license that was purchased.

In the PK-Sim® Research package only rat and human can be selected as species. In both the PK-Sim® Pre-Clinical and the PK-Sim® Clinical package all species are available.

Absorption Modules -- Since PK-Sim® version 3.0 this module has been available as a basic element implemented in all three PK-Sim® packages.

The Absorption Module simulates the gastro-intestinal transit and absorption process and serves the needs of scientists involved in biopharmaceutics and formulation development.

It is possible to simulate active transport in the intestine (transmembrane influx or efflux, Pgp-like efflux) as well as metabolism processes (multiple linear or saturable Michaelis-Menten) taking place in the gut wall.

Furthermore, different release kinetics (e.g. for controlled release) can be modeled selecting different pre-determined or user definable release functions for oral application.

Distribution Modules -- Model parameters (organ/plasma partition coefficients, permeabilities) are calculated from substance specific input parameters and can be adjusted independently.

Since version 4.0 of PK-Sim® the 'Rodgers and Rowland Model' is included for a more accurate prediction of the partition coefficients of ionized compounds.

This model takes electrostatic interactions of drugs with acidic phospholipids present in the cellular membrane into account, which is the reason why pK and pH values are included in the calculation of partition coefficients.

Metabolism & Excretion Modules -- Multiple metabolism and elimination processes in various organs and compartments can be simulated using this add-on module.

For example, biliary excretion can be described, allowing a realistic description of drugs that are subject to enterohepatic circulation.

PK-PD Module -- This module is an extension of PK-Sim® enabling the description of pharmacodynamic (PD) effects and thus the simulation of dose-response relationships.

As in conventional PK/PD modeling, a pharmacodynamic effect in dependence of the drug concentration can be defined.

Simulated concentration-time profiles for all organs are obtained, in addition to experimental plasma profiles, which can help researchers during the late optimization phase and preclinical development to identify specific effects (e.g. the relevance of active transport processes) and to guide the experimental efforts.

PK-Pop Module -- The PK-Pop module allows for the creation and simulation of a realistic ‘virtual population’ to assess the pharmacokinetic variability in a group of humans.

At the heart of this module are built-in databases containing information about the age and gender dependence of mean values and the variability of the relevant anatomical parameters such as body size, organ volume and blood flow (e.g. from the US NHANES III study).

Clearance Scaling Module -- With this module hepatic, renal and biliary clearances in a child under the age of 18 years can be estimated based on information about clearance values in adults.

In vitro ontogeny information as well as in vivo data of compounds, which undergo elimination by a single process, was used to build the clearance scaling module.

System Requirements

Operating Systems - Vista®, Windows XP®, Windows 2000®

Processor - Minimum: Pentium III, 500 MHz (1 GHz recommended for PK/PD and/or PK-Pop Module).

Memory - Minimum: 512 MB RAM (1024 MB recommended for PK/PD and/or PK-Pop Module).

Disk Space - Minimum: 100 MB (additional 120 MB required for PK-Pop examples).

Software - MS Excel® (For data export/import only).


Manufacturer Web Site Bayer PK-Sim

Price Contact manufacturer.

G6G Abstract Number 20460

G6G Manufacturer Number 104088