Monoclonal antibody disposition: a simplified PBPK model and its implications for the derivation and interpretation of classical compartment models

  • Ludivine Fronton
  • Sabine Pilari
  • Wilhelm Huisinga
Original Paper

Abstract

The structure, interpretation and parameterization of classical compartment models as well as physiologically-based pharmacokinetic (PBPK) models for monoclonal antibody (mAb) disposition are very diverse, with no apparent consensus. In addition, there is a remarkable discrepancy between the simplicity of experimental plasma and tissue profiles and the complexity of published PBPK models. We present a simplified PBPK model based on an extravasation rate-limited tissue model with elimination potentially occurring from various tissues and plasma. Based on model reduction (lumping), we derive several classical compartment model structures that are consistent with the simplified PBPK model and experimental data. We show that a common interpretation of classical two-compartment models for mAb disposition—identifying the central compartment with the total plasma volume and the peripheral compartment with the interstitial space (or part of it)—is not consistent with current knowledge. Results are illustrated for the monoclonal antibodies 7E3 and T84.66 in mice.

Keywords

mAb disposition PBPK Extravasation rate-limited tissue model Classical compartment model 

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Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Ludivine Fronton
    • 1
    • 2
    • 3
  • Sabine Pilari
    • 2
    • 4
    • 5
  • Wilhelm Huisinga
    • 6
  1. 1.Institute of Biochemistry and BiologyUniversität PotsdamPotsdamGermany
  2. 2.Graduate Research Training Program PharMetrX: Pharmacometrics & Computational Disease ModelingFreie Universität Berlin and Universität PotsdamBerlin/PotsdamGermany
  3. 3.F. Hoffmann-La Roche Ltd, pRED Pharmaceutical SciencesBaselSwitzerland
  4. 4.Department of Mathematics and Computer ScienceFreie Universität BerlinBerlinGermany
  5. 5.AbbVie GmbH & Co. KGLudwigshafen am RheinGermany
  6. 6.Institute of MathematicsUniversität PotsdamPotsdamGermany

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