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Preclinical PK/PD modeling and human efficacious dose projection for a glucokinase activator in the treatment of diabetes

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Abstract

Human Hexokinase IV, or glucokinase (GK), is a regulator of glucose concentrations in the body. It plays a key role in pancreatic insulin secretion as well as glucose biotransformation in the liver, making it a potentially viable target for treatment of Type 2 diabetes. Allosteric activators of GK have been shown to decrease blood glucose concentrations in both animals and humans. Here, the development of a mathematical model is presented that describes glucose modulation in an ob/ob mouse model via administration of a potent GK activator, with the goal of projecting a human efficacious dose and plasma exposure. The model accounts for the allosteric interaction between GK, the activator, and glucose using a modified Hill function. Based on model simulations using data from the ob/ob mouse and in vitro studies, human projections of glucose response to the GK activator are presented, along with dose and regimen predictions to maintain clinically significant decreases in blood glucose in a Type 2 diabetic patient. This effort serves as a basis to build a detailed mechanistic understanding of GK and its role as a therapeutic target for Type 2 diabetes, and it highlights the benefits of using such an approach in a drug discovery setting.

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Acknowledgments

The authors are grateful to Jonathan Almaden, Tom Carlson, Sharon Lostracco Johnson, Jocelyn Herrera Zoll, David Looper and Brett Simmons for technical support.

Author information

Author notes

  1. Michael G. Zager

    Present address: Model-Based Drug Development, Janssen Pharmaceutical Companies of Johnson & Johnson, 3210 Merryfield Row, San Diego, CA, 92121, USA

  2. Kirk Kozminski

    Present address: ADME and Bioanalysis Department, Ferring Research Institute, Inc., 4245 Sorrento Valley Blvd, San Diego, CA, 92121, USA

  3. Kathleen M. Ogilvie

    Present address: aTyr Pharma, Inc., 3545 John Hopkins Court, San Diego, CA, 92121, USA

Authors and Affiliations

  1. Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research and Development, 10646 Science Center Drive, San Diego, CA, USA

    Michael G. Zager & Kirk Kozminski

  2. Diabetes Biology, Pfizer Worldwide Research and Development, 10646 Science Center Drive, San Diego, CA, USA

    Bernadette Pascual & Kathleen M. Ogilvie

  3. Biochemical Pharmacology, Pfizer Worldwide Research and Development, 10646 Science Center Drive, San Diego, CA, USA

    Shaoxian Sun

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  1. Michael G. Zager
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Correspondence to Michael G. Zager.

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Zager, M.G., Kozminski, K., Pascual, B. et al. Preclinical PK/PD modeling and human efficacious dose projection for a glucokinase activator in the treatment of diabetes. J Pharmacokinet Pharmacodyn 41, 127–139 (2014). https://doi.org/10.1007/s10928-014-9351-7

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  • DOI: https://doi.org/10.1007/s10928-014-9351-7

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