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A Mathematical Model of the Effect of Immunogenicity on Therapeutic Protein Pharmacokinetics

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Abstract

A mathematical pharmacokinetic/anti-drug-antibody (PK/ADA) model was constructed for quantitatively assessing immunogenicity for therapeutic proteins. The model is inspired by traditional pharmacokinetic/pharmacodynamic (PK/PD) models, and is based on the observed impact of ADA on protein drug clearance. The hypothesis for this work is that altered drug PK contains information about the extent and timing of ADA generation. By fitting drug PK profiles while accounting for ADA-mediated drug clearance, the model provides an approach to characterize ADA generation during the study, including the maximum ADA response, sensitivity of ADA response to drug dose level, affinity maturation rate, time lag to observe an ADA response, and the elimination rate for ADA–drug complex. The model also provides a mean to estimate putative concentration–time profiles for ADA, ADA–drug complex, and ADA binding affinity-time profile. When simulating ADA responses to various drug dose levels, bell-shaped dose–response curves were generated. The model contains simultaneous quantitative modeling and provides estimation of the characteristics of therapeutic protein drug PK and ADA responses in vivo. With further experimental validation, the model may be applied to the simulation of ADA response to therapeutic protein drugs in silico, or be applied in subsequent PK/PD models.

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ACKNOWLEDGMENTS

We would like to thank the anonymous reviewers, Scott Fountain, Kenneth Luu, Mary Spilker, and Michael Zager for their valuable suggestions. We thank the PDM department colleagues and especially the immunogenicity strategy group (Li Xue, Bonita Rup, Pratap Singh, John Harrold, Denise O'Hara, Boris Gorovits, Jim McNally, Mengmeng Wang, Anup Zutshi, Ryan Nolan, Michel Awwad, and Anson Abraham) for their help and suggestions.

Conflict of Interest

All authors are employed by Pfizer Inc. This work was partially presented as a poster presentation at the 2012 AAPS National Biotechnology Conference, May 21–22 in San Diego, CA, USA. P. V. receives royalties from the University of Washington Center for Commercialization, the licensor of the SAAM II software.

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Authors and Affiliations

  1. Pharmacokinetics, Dynamics, and Metabolism, Pfizer Inc, 10646 Science Center Drive, CB4, San Diego, California, 92121-1150, USA

    Xiaoying Chen, Eugenia Kraynov, Bing Kuang & Paolo Vicini

  2. Pharmacokinetics, Dynamics, and Metabolism, Pfizer Inc, 35 Cambridge Park Drive, Cambridge, Massachusetts, 02140, USA

    Chuenlei Parng

  3. Pharmacokinetics, Dynamics, and Metabolism, Pfizer Inc, 1 Burtt Road, Andover, Massachusetts, 01810, USA

    Timothy Hickling

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  1. Xiaoying Chen
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Correspondence to Paolo Vicini.

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Chen, X., Hickling, T., Kraynov, E. et al. A Mathematical Model of the Effect of Immunogenicity on Therapeutic Protein Pharmacokinetics. AAPS J 15, 1141–1154 (2013). https://doi.org/10.1208/s12248-013-9517-z

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  • DOI: https://doi.org/10.1208/s12248-013-9517-z

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