Friday, 30. January 2009

PK-Sim® Version 4.1 is now available!

This new version provides many considerable new features that have been requested by our customers and partners. Major improvements are a completely new model structure allowing a better description of large and protein bound molecules, a completely new concept called “Specific Clearance” that allows scaling of clearance between individuals and species by a single mouse click.

What’s New in PK-Sim® Version 4.1?

1.    Additional Model Structure for a Better Description of Special  Molecule Classes

In the standard PK-Sim® model structure an organ is represented by three compartments: the intracellular space, blood cells and a compartment lumping plasma and interstitial space. With PK-Sim® 4.1 the user can switch to the “4 subcompartments per organ” model. In this model structure, the interstitial subcompartment is separated from the plasma by the vascular endothelium. The barrier function of the vascular epithelium is of particular importance for large molecules such as therapeutic proteins (antibodies, etc.) and highly protein bound compounds (NSAIDs, etc).

2.    Switch of Species and New Concept “Specific Clearance”

The new concept of “Specific Clearance” simplifies the extrapolation between individuals and species. When switching from one species to another the Specific Clearance automatically scales clearance according to organ volume, number of cells or microsomal protein mass of relevant tissue. Furthermore, switching of species is technically simplified as active processes are not deleted and all explicitly specified parameter settings remain unchanged except for species specific parameters. 

3.    Scaling of Vmax values

The concept of “Specific Clearance” was extended to the Michaelis-Menten kinetics parameter Vmax, converting this assay dependent value into a specific in vivo parameter, termed VmaxSpec. This parameter is normalized to the cellular volume of the organ or compartment where the process occurs. 

4.    New Units for in vitro Data to Determine Enzyme Kinetics

Several new units for specification enzyme activity by means of clearance or Michaelis-Menten kinetics based on in-vitro data have been added. For calculation of the corresponding specific clearances and specific Vmax values input of number of cells or amount cellular protein is necessary and is achieved in a newly integrated Cell Density & Protein Content Tab in PK-Sim®. Furthermore, it is now possible to input in vitro data from assays using recombinant CYP450 by

  • defining an in vitro clearance for a first order process.
  • specifying an in vitro Vmax value for a saturable Michaelis Menten process.

5.    Calculation of Intestinal Permeability from in-vitro Data

It is now possible to use in-vitro permeability data for the calculation of intestinal permeability. The corresponding correlation function is parametrized on the basis of relevant data provided by the customer.

6.    Additional Calculation Methods for Plasma/Organ Partition Coefficients

  • Schmitt Model: This approach considers electrostatic interactions between charged compounds and acidic phospholipids at physiological pH. The underlying mechanistic equations are universally applicable to neutral, acidic, basic or multiple charged substances. pH gradients between cellular space and plasma account for differences in unbound concentrations for weak acids and bases. This differential accounts for a charge dependent distribution between two (sub)compartments with different pH values.
  • Poulin & Theil Model: Input data for the calculation of tissue/plasma partition coefficients are in vitro data on drug lipophilicity and plasma protein binding as well as physiological parameters for tissue volumes and composition. The mechanistic basis of the Poulin and Theil Model is that the compound homogeneously distributes into tissue and plasma which are comprised of a mixture of lipids, water, and plasma proteins. The model distinguishes between neutral lipids and phospholipids, the latter having a lipo-hydrophilicity similar to a mixture of 30 % neutral lipids and 70 % water.
  • Berezhkovskiy Model: The equation provided by Berezhkovskiy for the calculation of tissue to plasma partition coefficients represents a modification of the one described by Poulin and Theil. The input parameters, however, are identical to the ones used in the Poulin and Theil Model.

7.    New Species – Minipig

Besides the established animal models of the monkey, dog, rat, and mouse PK-Sim® 4.1 now includes a minipig model.

8.    New Compartment in Human Model - Saliva

The saliva has been shown to be a useful alternative to plasma for routine monitoring of several drug substances. Therefore, saliva was added as a new compartment and the concentration-time profile in this compartment is routinely calculated.

9.    New Application Routes

  • Subcutaneous 
  • Dermal

10.    Reorganization of Graphical User Interface

Many additional parameters are now accessible such as, for example, volume fraction of lipid, water and protein or cell density & protein content of organs.

11.    Summary Plots

This additional plot window is able to present the compilation of different simulations within one plot. This is especially useful to summarize the most relevant simulations at a glance.

12.    Project Report

It is now possible to automatically generate a report of key parameter settings in Html or as plain text format.

13.    Redesign of Compound Window

Two new input fields have been added for all of the following parameters, namely Lipophilicity, Protein Binding, Solubility, Fraction Unbound, Plasma Clearance and Renal Clearance. For each parameter, one entry is reserved for the experimentally measured value and the second entry is used to enter reasonable adjustments to these parameters for the adaptation of simulation results.

14.    Minor Improvements

  • Data import: It is possible to rename Observed Data during data import.
  • Experimental data: Experimental data used in a simulation are displayed in the graphical tree view.
  • Project: A Project file is opened in read-only mode in case the file is already in use by another user.
  • Plot Window: It is now possible for the user to scale the plot axes manually.
  • User Defined Solubility: Reset option for pH-solubility pair.

April 12, 2017

Two new publications regarding PBPK modeling! : A pregnancy PBPK model has been developed, and evaluated for renally cleared drugs.

» More

March 28, 2017

Published in npj Systems Biology and Applications: Translational learning from clinical studies predicts drug pharmacokinetics across patient populations

» More

December 19, 2016

New publications regarding PBPK modeling: Elderly, Isoniazid, DDI and Diabetes. In addition: A white paper regarding good practices in drug discovery and development

» More

» All News

October 14, 2017

ACoP8 Conference, October 15-18 2017 in Florida

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June 25, 2017

14th European ISSX Meeting, June 26-29 2017 in Cologne

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June 05, 2017

PAGE Meeting 2017, June 06-09, Budapest, Hungary

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» All Events