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Dopamine D2 Receptor Occupancy as a Predictor of Catalepsy in Rats: A Pharmacokinetic-Pharmacodynamic Modeling Approach

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Abstract

Objectives

Dopamine D2 receptor occupancy (D2RO) is the major determinant of efficacy and safety in schizophrenia drug therapy. Excessive D2RO (>80%) is known to cause catalepsy (CAT) in rats and extrapyramidal side effects (EPS) in human. The objective of this study was to use pharmacokinetic and pharmacodynamic modeling tools to relate CAT with D2RO in rats and to compare that with the relationship between D2RO and EPS in humans.

Methods

Severity of CAT was assessed in rats at hourly intervals over a period of 8 h after antipsychotic drug treatment. An indirect response model with and without Markov elements was used to explain the relationship of D2RO and CAT.

Results

Both models explained the CAT data well for olanzapine, paliperidone and risperidone. However, only the model with the Markov elements predicted the CAT severity well for clozapine and haloperidol. The relationship between CAT scores in rat and EPS scores in humans was implemented in a quantitative manner. Risk of EPS not exceeding 10% over placebo correlates with less than 86% D2RO and less than 30% probability of CAT events in rats.

Conclusion

A quantitative relationship between rat CAT and human EPS was elucidated and may be used in drug discovery to predict the risk of EPS in humans from D2RO and CAT scores measured in rats.

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ACKNOWLEDGMENTS

This research article was prepared within the framework of project no. D2-104 of the Dutch Top Institute Pharma (Leiden, The Netherlands; www.tipharma.com). The authors acknowledge Dr. Megens from Janssen Research and Development, a division of Janssen Pharmaceutica NV, Beerse, Belgium, for the valuable discussion on animal pharmacology models. The authors have no conflicts of interest that are directly relevant to the contents of this research article.

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Authors and Affiliations

  1. Division of Pharmacokinetics, Toxicology and Targeting, University of Groningen, University Centre for Pharmacy, Antonius Deusinglaan 1, Groningen, 9713 AV, The Netherlands

    Martin Johnson, Magdalena Kozielska, Venkatesh Pilla Reddy, Geny M. M. Groothuis & Johannes H. Proost

  2. Advanced PK-PD Modeling and Simulation, Janssen Research and Development, A Division of Janssen Pharmaceutica NV, Beerse, Belgium

    An Vermeulen

  3. Worldwide Research & Development Pfizer Inc., Groton, CT, USA

    Hugh A. Barton & Sarah Grimwood

  4. Pharmacokinetics, Pharmacodynamics & Drug Metabolism Merck Sharp & Dohme, Oss, The Netherlands

    Rik de Greef

  5. Division of Pharmacology, Leiden Academic Center for Drug Research, Leiden, The Netherlands

    Meindert Danhof

Authors
  1. Martin Johnson
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  2. Magdalena Kozielska
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  3. Venkatesh Pilla Reddy
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  4. An Vermeulen
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  5. Hugh A. Barton
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  6. Sarah Grimwood
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  7. Rik de Greef
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  8. Geny M. M. Groothuis
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  9. Meindert Danhof
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  10. Johannes H. Proost
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Corresponding author

Correspondence to Johannes H. Proost.

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Johnson, M., Kozielska, M., Pilla Reddy, V. et al. Dopamine D2 Receptor Occupancy as a Predictor of Catalepsy in Rats: A Pharmacokinetic-Pharmacodynamic Modeling Approach. Pharm Res 31, 2605–2617 (2014). https://doi.org/10.1007/s11095-014-1358-7

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  • DOI: https://doi.org/10.1007/s11095-014-1358-7

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