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Estimating drug potency in the competitive target mediated drug disposition (TMDD) system when the endogenous ligand is included.

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Abstract

Predictions for target engagement are often used to guide drug development. In particular, when selecting the recommended phase 2 dose of a drug that is very safe, and where good biomarkers for response may not exist (e.g. in immuno-oncology), a receptor occupancy prediction could even be the main determinant in justifying the approved dose, as was the case for atezolizumab. The underlying assumption in these models is that when the drug binds its target, it disrupts the interaction between the target and its endogenous ligand, thereby disrupting downstream signaling. However, the interaction between the target and its endogenous binding partner is almost never included in the model. In this work, we take a deeper look at the in vivo system where a drug binds to its target and disrupts the target’s interaction with an endogenous ligand. We derive two simple steady state inhibition metrics (SSIMs) for the system, which provides intuition for when the competition between drug and endogenous ligand should be taken into account for guiding drug development.

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Acknowledgements

We would like to thank Mirjam Trame for co-organizing the 2018 Novartis-Academia Quantitative Hackathon, where this work began and we would also like to thank our other Hackathon team members, Ryan Richards and Ruidi Chen. In addition, Matt Fidler helped with RxODE for the model simulations; Khachik Sargasyan helped us think through how to perform the global sensitivity analysis; Bert Peletier helped with the organizational structure of this manuscript; Martin Fink helped with clarifying the key message and model description; and Jaeyeon Kim helped with parameter selection and thinking through the implications of this work.

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Author notes

  1. Begum Alaybeyoglu

    Present address: Javelin Biotech Inc, Woburn, MA, 01801, USA

Authors and Affiliations

  1. Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA

    Begum Alaybeyoglu

  2. Department of Systems Biology, Harvard Medical School, Boston, MA, 02115, USA

    Ho Wa (Jacky) Cheng

  3. Boston University, Boston, MA, 02215, USA

    Kshama A. Doshi

  4. Sutro Biopharma, Inc. South, San Francisco, CA, 94080, USA

    Kshama A. Doshi

  5. Wake Forest Institute for Regenerative Medicine, Wake Forest University, Winston-Salem, NC, 27101, USA

    Vishruti Makani

  6. KBI Biopharma, Inc, Durham, NC, 27703, USA

    Vishruti Makani

  7. Novartis Institute for BioMedical Research, 220 Massachusetts Avenue, Cambridge, MA, 02139, USA

    Andrew M. Stein

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  1. Begum Alaybeyoglu
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  2. Ho Wa (Jacky) Cheng
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  3. Kshama A. Doshi
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Correspondence to Andrew M. Stein.

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Alaybeyoglu, B., Cheng, H.W.(., Doshi, K.A. et al. Estimating drug potency in the competitive target mediated drug disposition (TMDD) system when the endogenous ligand is included.. J Pharmacokinet Pharmacodyn 48, 447–464 (2021). https://doi.org/10.1007/s10928-020-09734-9

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  • DOI: https://doi.org/10.1007/s10928-020-09734-9

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