Dopamine D2 Receptor Occupancy as a Predictor of Catalepsy in Rats: A Pharmacokinetic-Pharmacodynamic Modeling Approach
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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.
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.
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.
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.
KEY WORDScatalepsy dopamine D2 receptor antagonist EPS Markov model schizophrenia
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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