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    GastroPlus™

    PBPK modeling software – from discovery through
    regulatory filings…

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    Biologics

    What is the Biologics Module?

    We are pleased to offer PBPK models for large molecules (biologics). The Biologics Module simulates the systemic absorption and pharmacokinetics of biologics – for both monoclonal antibodies (mAb) and NEW! antibody-drug conjugates (ADCs). In the current implementation, both mAbs and ADCs administered as an intravenous bolus dose, intravenous infusion, subcutaneous (SQ), and NEW! intramuscular (IM) injections (both bolus and controlled release) can be modeled.

    As with other GastroPlus modules, there is no equation or code writing required. A schematic diagram of how the different organs are connected to one another is shown below. All major organs are connected in an anatomical fashion with plasma flow represented by blue solid arrows and lymph flow by red dashed arrows.

    The lymph node collects the lymphatic drainage from organs and lymph fluid is returned to the systemic circulation. Each organ in the PBPK model is divided into three major compartments representing the vascular, endosomal, and interstitial spaces.

    Resources

    Biologics
    vascular space

    PBPK models for monoclonal antibodies (mAb) - processes considered:

    • Convective transport and fluid phase endocytosis describing uptake of antibody into the tissue
    • mAb-FcRn (neonatal FC receptor) binding & recycling – including pH-dependent binding kinetics
    • Target mediated elimination in the interstitial space to include the influence of specific antigen-mAb interactions on mAb disposition
    • Within the endosomal space, the competition for binding to FcRn between endogenous IgG and the therapeutic mAb
    • mAb administration by either intravenous (IV), subcutaneous (SQ), or intramuscular injections
    • Default physiology parameters for humans & animals – with the flexibility to create custom models

    PBPK models for antibody-drug conjugates (ADCs) - processes considered:

    • Distribution and elimination processes of multiple ADC species with different DAR (drug-to-antibody ratio)
    • Clearance defined through nonspecific mechanisms
    • Binding to target receptor, internalize, and be cleared in the cell lysosome
    • Release and clearance of the toxin molecule
      • Toxins can fall off antibody due to deconjugation
      • Released toxins can be cleared through metabolism or renally
    • Two types of deconjugation models included:
      • Series of transit processes to describe deconjugation from high to low DARs
      • Average DAR used to describe deconjugation step