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Permeability | Binding | Metabolism | Transport

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Your modeling tool for IVIVE of absorption and systemic clearance/distribution processes…

For over 20 years, significant research has been devoted to in vitro permeability (e.g., Caco-2 assays) and hepatocyte systems, with several guidelines being published and all pharmacopeia describing appropriate methods for testing. Unfortunately, these experiments are expensive, and since you don’t have a lot of time or material available, how do you prioritize which compounds to test early in your project? Once you have identified a few promising leads, is your experimental design robust enough to capture all of the relevant information you need? And, after you collect the data and compile your apparent permeability or intrinsic clearance, are you certain you are not overlooking anything?

Enter MembranePlus™, the industry’s leading mechanistic in vitro permeability & hepatocyte modeling software. MembranePlus is helpful for:

  • Users of GastroPlus™ looking to better inform inputs (e.g., lysosomal trapping, diffusional clearances, biliary excretion) for more accurate in vivo absorption and systemic clearance/distribution predictions with the Advanced Compartmental Absorption and Transit (ACAT™) and PBPK models
  • Discovery scientists looking to categorize compounds into high and low permeability classes
  • DMPK researchers that focus on in vitro transporter/metabolism kinetic studies – model your measured data to capture all relevant information from the expensive experiments you are running
  • CROs which provide in vitro permeability (Caco-2, PAMPA, or MDCK) or hepatocyte services, to assist with the optimization of the experimental design for client studies

The two modules of MembranePlus™ are:

What are we providing with MembranePlus?

We have always been dedicated to carefully implement the best theories and develop novel approaches within the MembranePlus permeability & hepatocyte models. You enter limited physicochemical & metabolism/transporter data (if applicable), set up your permeability/hepatocyte experiment, and MembranePlus handles the rest:

  • Simple, intuitive user interface
  • Model optimization
  • Strong integration with our other tools, like ADMET Predictor® and GastroPlus
  • High-quality plots & figures for reporting purposes
  • Excellent customer support

The in vitro processes which are considered in the MembranePlus simulations, and the methods we’ve introduced to parameterize them, are too numerous to list here – instead, take a peek at the MembranePlus datasheet for more details.

How can MembranePlus help me?

The MembranePlus permeability modeling platform has been utilized by companies across various industries and departments since 2014. MembranePlus has several primary applications:

Simulation of in vitro permeability & hepatocyte concentrations

  • Screen compound libraries and prioritize compounds for testing
  • Predict various permeability (e.g., paracellular, transcellular) & hepatocyte (e.g., diffusional clearance, lysosomal trapping, biliary excretion) processes
  • Estimate different intracellular concentrations, including:
    • Membrane
    • Cytosol
    • Lysosome
  • Assess impact of experimental variability on the predicted outcomes

Analysis of measured in vitro experimental data

  • Identify paracellular vs. transcellular permeability values
  • Calculate in vitro Km and Vmax for enzymes and transporters
  • Determine the impact of lysosomal trapping
  • Assess biliary excretion routes with sandwich hepatocyte assays
  • Fit parameters to build a robust model and unlock important insight from the data

The program provides several simulation modes to help you achieve your goals:

  • Single simulation – based on your drug properties (whether measured or predicted through ADMET Predictor) and permeability or hepatocyte experimental setup, easily run a simulation to predict the time course changes in concentrations (e.g., apical, basolateral, cellular or lysosomal).
  • Parameter sensitivity analysis (PSA) – during early drug development, researchers have a large number of compounds to evaluate and limited resources. With Parameter Sensitivity Analysis, quickly assess the impact of changes to certain properties (e.g., physicochemical or experimental) on critical endpoints. This can help guide your resource allocation plans and identify which permeability or hepatocyte experiments should be done next.
  • Batch mode – quickly screen a library of compounds based on predicted permeability or run the same compound through a series of different Caco-2, PAMPA, MDCK, or hepatocyte experiments. Easily prioritize compounds in any way you like: from high to low permeability, based upon potential issues with lysosomal trapping, etc.

Check out various case studies using MembranePlus and GastroPlus by reviewing publications and webinars on our Resource Center.

What's new in version 2?

Check out the exciting new features in MembranePlus v2! This version takes modeling of in vitro systems to the next level, allowing you to capture all relevant information from your experiments.

  • New cellular membrane models:
    • Mechanistic models of sandwich hepatocyte assays (with biliary excretion processes)
    • Mechanistic models of suspended hepatocyte assays
  • Improved ADMET Predictor® Module integration:
    • Updated models from ADMET Predictor version 8.1
    • Prediction of Km/Vmax for metabolism by cytochrome P450 enzymes (CYPs), including isoforms 1A2, 2C9, 2C19, 2D6, and 3A4
    • IVIVE settings for conversion to either intestinal cell monolayers or hepatocytes.
    • Allow membrane model to be specified upon structure import.
    • Classification models to predict whether imported compounds are substrates for Pgp and/or OATP1B1.
  • New simulation outputs:
    • Fu Cell – this new output provides an estimate of Fu,Enterocytes for use in GastroPlus PBPK models. This improves the prediction of absorption & pharmacokinetics for compounds exhibiting lysosomal trapping and/or high binding in enterocytes causing extended Tmax values.
    • CLdiff – the passive diffusional clearance parameter is an output that can be used in connection with GastroPlus PBPK models to define the permeability-surface area product (PStc) in PBPK tissues.
  • General features:
    • Excel spreadsheet output formats for all simulations modes
    • Cytosolic fraction unbound for intracellular protein binding
    • New tutorials with step-by-step instructions
    • New installation option (terminal services)
    • Bug fixes

View the full MembranePlus v2 release notes.

MembranePlus v2 is now available for download – instructions can be found here!

How do I move forward from here?

Join your peers around the world and begin working with MembranePlus to unlock important information from your in vitro permeability (Caco-2, PAMPA, and MDCK cells) and hepatocyte studies.

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