The AAPS Journal

, Volume 16, Issue 4, pp 810–842 | Cite as

Simplification of Complex Physiologically Based Pharmacokinetic Models of Monoclonal Antibodies

  • Mohamed Elmeliegy
  • Philip Lowe
  • Wojciech Krzyzanski
Research Article

Abstract

Monoclonal antibodies (mAbs) exhibit biexponential profiles in plasma that are commonly described with a standard two-compartment model with elimination from the central compartment. These models adequately describe mAb plasma PK. However, these models ignore elimination from the peripheral compartment. This may lead to underestimation of the volume of distribution of the peripheral compartment and thus over-predicts concentration in the peripheral compartment. We developed a simple and physiologically relevant model that incorporates information on binding and dissociation rates between mAb and FcRn receptor, mAb uptake, reflection, and catabolic degradation. We employed a previously published PBPK model and, with assumptions regarding rates of processes controlling mAb disposition, reduced the complex PBPK model to a simpler circular model with central, peripheral, and lymph compartments specifying elimination from both central and peripheral. We successfully applied the model to describe the PK of an investigational mAb. Our model presents an improvement over standard two-compartmental models in predicting whole-body average tissue concentrations while adequately describing plasma PK with minimal complexity and physiologically more meaningful parameters.

Key words

compartmental models monoclonal antibodies PBPK 

Notes

Acknowledgments

This work was supported by NIH Grant GM57980 and the University at Buffalo-Novartis Fellowship. We would like to acknowledge thoughtful comments from Dr. Joseph P. Balthasar and Dr. Yang Chen.

Conflict of Interest

The authors declare no conflict of interest

Supplementary material

12248_2014_9591_MOESM1_ESM.docx (894 kb)
ESM 1 (DOCX 894 kb)

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Copyright information

© American Association of Pharmaceutical Scientists 2014

Authors and Affiliations

  • Mohamed Elmeliegy
    • 1
  • Philip Lowe
    • 2
  • Wojciech Krzyzanski
    • 1
  1. 1.Department of Pharmaceutical Sciences, School of Pharmacy & Pharmaceutical SciencesUniversity at Buffalo—State University of New YorkBuffaloUSA
  2. 2.Novartis Pharma AGBaselSwitzerland

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