A Physiologically-Based Pharmacokinetic Model for the Prediction of "Half-Life Extension" and "Catch and Release" Monoclonal Antibody Pharmacokinetics.

CPT: Pharmacometrics & Systems Pharmacology
Hannah JonesRobert Webster

Abstract

Monoclonal antibodies (mAbs) can be engineered to have "extended half-life" and "catch and release" properties to improve target coverage. We have developed a mAb physiologically-based pharmacokinetic model that describes intracellular trafficking, neonatal Fc receptor (FcRn) recycling, and nonspecific clearance of mAbs. We extended this model to capture target binding as a function of target affinity, expression, and turnover. For mAbs engineered to have an extended half-life, the model was able to accurately predict the terminal half-life (82% within 2-fold error of the observed value) in the human FcRn transgenic (Tg32) homozygous mouse and human. The model also accurately captures the trend in pharmacokinetic and target coverage data for a set of mAbs with differing catch and release properties in the Tg32 mouse. The mechanistic nature of this model allows us to explore different engineering techniques early in drug discovery, potentially expanding the number of "druggable" targets.

References

Dec 13, 2005·Annals of Biomedical Engineering·Gregory Z FerlJoseph J DiStefano
Jul 20, 2007·Journal of Pharmacokinetics and Pharmacodynamics·Amit Garg, Joseph P Balthasar
Sep 24, 2009·Journal of Pharmaceutical Sciences·Shweta R UrvaJoseph P Balthasar
Sep 8, 2010·Clinical Pharmacokinetics·Nathanael L Dirks, Bernd Meibohm
Mar 17, 2011·MAbs·Tomoyuki IgawaKunihiro Hattori
Dec 7, 2011·Journal of Pharmacokinetics and Pharmacodynamics·Dhaval K Shah, Alison M Betts
Feb 2, 2012·The Journal of Biological Chemistry·Javier Chaparro-RiggersArvind Rajpal
Jan 10, 2013·Clinical Pharmacokinetics·Miroslav DostalekManoranjenni Chetty
May 15, 2013·PloS One·Tomoyuki IgawaKunihiro Hattori
Dec 30, 2014·The Journal of Biological Chemistry·M Jack BorrokPing Tsui
Sep 4, 2015·Clinical and Experimental Immunology·Julie E LedgerwoodUNKNOWN VRC 602 Study Team
Apr 5, 2016·International Journal of Pharmaceutics·Patrick M Glassman, Joseph P Balthasar
Jul 6, 2016·Journal of Pharmacokinetics and Pharmacodynamics·Patrick M Glassman, Joseph P Balthasar
Aug 25, 2016·Current Pharmaceutical Biotechnology·Futa MimotoKunihiro Hattori
Jan 5, 2018·MAbs·Hélène Kaplon, Janice M Reichert
Aug 25, 2019·Biomolecules·Yao-Yun FanHendrik Neubert
Aug 30, 2019·CPT: Pharmacometrics & Systems Pharmacology·Hannah M JonesRobert Webster

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Citations

Apr 4, 2021·International Journal of Molecular Sciences·Timothy Qi, Yanguang Cao

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Methods Mentioned

BETA
transgenic
surface plasmon resonance

Software Mentioned

Phoenix WinNonlin
J2 Dynamic Modeling and Optimization Software

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