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Current Approaches for Predicting Human PK for Small Molecule Development Candidates: Findings from the IQ Human PK Prediction Working Group Survey

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Abstract

Accurate prediction of human clearance (CL) and volume of distribution at steady state (Vd,ss) for small molecule drug candidates is an essential component of assessing likely efficacious dose and clinical safety margins. In 2021, the IQ Consortium Human PK Prediction Working Group undertook a survey of IQ member companies to understand the current PK prediction methods being used to estimate these parameters across the pharmaceutical industry. The survey revealed a heterogeneity in approaches being used across the industry (e.g., the use of allometric approaches, differing incorporation of binding terms, and inconsistent use of empirical correction factors for in vitro-in vivo extrapolation, IVIVE), which could lead to different PK predictions with the same input data. Member companies expressed an interest in improving human PK predictions by identifying the most appropriate compound-class specific methods, as determined by physiochemical properties and knowledge of CL pathways. Furthermore, there was consensus that increased understanding of the uncertainty inherent to the compound class-dependent prediction would be invaluable in aiding communication of human PK and dose uncertainty at the time of candidate nomination for development. The human PK Prediction Working Group is utilizing these survey findings to help interrogate clinical IV datasets from across the IQ consortium member companies to understand PK prediction accuracy and uncertainty from preclinical datasets.

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Acknowledgements

The authors thank the IQ Secretariat and the Translational ADME Leadership Group for their support of this work. Specifically, we thank Svetlana Lyapustina, Maja Leah Marshall, and Jamie Vergis for their work in designing, conducting, and reporting the survey. Additionally, we would like to recognize Dr Chris Gibson for his scientific insights and enthusiastic sponsorship of the Human PK Prediction Working Group.

Author information

Author notes

  1. Kevin DeMent

    Present address: XinThera, Inc., San Diego, CA, USA

  2. Robin McDougall

    Present address: Repare Therapeutics, Quebec City, Canada

  3. James Baker

    Present address: Blueprint Medicines, Cambridge, MA, USA

Authors and Affiliations

  1. The Healthcare Business of Merck KGaA, Frankfurter Str. 250, Postcode D50/902, 64293, Darmstadt, Germany

    Carl Petersson

  2. Eli Lilly and Company, Indianapolis, IN, USA

    Xin Zhou

  3. Novartis, Basel, Switzerland

    Joerg Berghausen

  4. GSK, Brentford, UK

    David Cebrian

  5. AstraZeneca, Cambridge, UK

    Michael Davies

  6. Takeda Pharmaceuticals International, Inc., Deerfield, IL, USA

    Kevin DeMent & Charles Rotter

  7. Vertex Pharmaceuticals Incorporated, Boston, MA, USA

    Peter Eddershaw

  8. Bristol-Myers Squibb, New York, NY, USA

    Arian Emami Riedmaier & Zheng Yang

  9. AbbVie Inc., North Chicago, IL, USA

    Alix F. Leblanc

  10. F. Hoffman-La Roche Ltd., Basel, Switzerland

    Nenad Manveski & Neil Parrott

  11. Agios Pharmaceuticals, Cambridge, MA, USA

    Punit Marathe

  12. Sanofi, Paris, France

    Panteleimon D. Mavroudis

  13. Alnylam Pharmaceuticals, Inc., Cambridge, MA, USA

    Robin McDougall

  14. Bayer AG, Leverkusen, Germany

    Andreas Reichel

  15. Pfizer, Inc., New York, NY, USA

    David Tess

  16. Janssen Research and Development, LLC, Raritan, NJ, USA

    Laurie P. Volak

  17. Sunovion Pharmaceuticals, Inc., Marlborough, MA, USA

    Guangqing Xiao

  18. Merck and Co., Inc, Kenilworth, NJ, USA

    James Baker

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Petersson, C., Zhou, X., Berghausen, J. et al. Current Approaches for Predicting Human PK for Small Molecule Development Candidates: Findings from the IQ Human PK Prediction Working Group Survey. AAPS J 24, 85 (2022). https://doi.org/10.1208/s12248-022-00735-9

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