Pharmacokinetic-pharmacodynamic modeling of the relationship between D2 receptor occupancy and catalepsy in rats:Predicting extrapyramidal side effects in humans

Objectives: Dopamine D2 receptor occupancy (D2RO) is the major determinant of efficacy and safety in schizophrenia drug therapy (1,2). Excessive D2RO (>80 %) is known to cause catalepsy (CAT) in rats and extrapyramidal side effects (EPS) in human(3). The relationship between CAT scores in rats and EPS events in human is not yet clear. The objective of this study was to use pharmacokinetic and pharmacodynamic (PK-PD) modeling tools to relate CAT with D2RO in rats and compare that with the relationship between D2RO and EPS in human. Methods: Severity of CAT as an ordered categorical observation was assessed in rats at hourly intervals over a period of 8 hours after antipsychotic drug treatment. D2RO was predicted using previously developed hybrid physiology-based pharmacokinetic and pharmacodynamic (PBPKPD) models to describe the relationship between drug exposure in plasma and brain with D2RO in rats for olanzapine (OLZ), paliperidone (PAL), risperidone (RIS) (4,5). An indirect response model (IDR) combined with Markov element was used to describe the relationship between D2RO and CAT scores. We also compared the probability of CAT with the probability of EPS events in humans at steady-state conditions, as predicted using the PK-PD model proposed by Reddy et al (6). The relationship between D2RO and probability of CAT in rats was related to the D2RO-EPS relationship in humans using a polynomial equation. Results: The IDR model with Markov elements explained the CAT data well. Kin, Kout, RO50 and baseline probabilities were estimated with good precision. The relationship between CAT scores in rat and EPS scores in humans was elucidated in a quantitative manner. The probability of having EPS for 0% D2RO is approximately 5%, which shows the effect placebo on EPS. The risk of EPS does not exceed 10% over placebo correlates with less than 86% D2RO and less than 30% probability of CAT events in rats. Conclusion: The relationship between D2RO and CAT scores was elucidated using IDR with Markov elements. A quantitative relationship between CAT as observed in rats and EPS as observed in humans was elucidated and may be used in drug discovery to predict the risk of EPS in humans from D2RO and CAT scores in rats. References: [1] Howes OD, Kapur S. The Dopamine Hypothesis of Schizophrenia: Version III - The Final Common Pathway. 2009;35(3):549-62. [2] Kapur S, Remington G, Jones C, Wilson A, DaSilva J, Houle S, et al. High levels of dopamine D-2 receptor occupancy with low-dose haloperidol treatment: A PET study. American Journal of Psychiatry 1996 Jul;153(7):948-50. [3] Horacek J, Bubenikova-Valesova V, Kopecek M, Palenicek T, Dockery C, Mohr P, et al. Mechanism of action of atypical antipsychotic drugs and the neurobiology of schizophrenia. CNS Drugs 2006;20(5):389-409. [4] Johnson M, Kozielska M, Reddy VP, Vermeulen A, Li C, Grimwood S, et al. Mechanism-Based Pharmacokinetic-Pharmacodynamic Modeling of the Dopamine D(2) Receptor Occupancy of Olanzapine in Rats. Pharm Res 2011 Oct;28(10):2490-504. [5] Kozielska M, Johnson M, Reddy VP, Vermeulen A, Li C, Grimwood S, et al. Pharmacokinetic-Pharmacodynamic Modeling of the D2 and 5-HT2A Receptor Occupancy of Risperidone and Paliperidone in Rats. Pharm Res 2011;Accepted. [6] Reddy VP, Petersson K.J., Suleiman AA, Vermeulen A, Proost JH, Friberg LE. Pharmacokinetic-Pharmacodynamic Modeling of Severity Levels of Extrapyramidal Side Effects with Markov Property. Manuscript in Preparation 2012