title: Dopamine D2 receptor occupancy as a predictor of catalepsy in rats: a pharmacokinetic-pharmacodynamic modeling approach.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Pharmacokinetics, Toxicology and Targeting, University of Groningen, University Centre for Pharmacy, Antonius Deusinglaan 1, Groningen, 9713 AV, The Netherlands.
authors.forename: Martin
authors.initials: M
authors.lastname: Johnson
authors.forename: Magdalena
authors.initials: M
authors.lastname: Kozielska
authors.forename: Venkatesh
authors.initials: V
authors.lastname: Pilla Reddy
authors.forename: An
authors.initials: A
authors.lastname: Vermeulen
authors.forename: Hugh A
authors.initials: HA
authors.lastname: Barton
authors.forename: Sarah
authors.initials: S
authors.lastname: Grimwood
authors.forename: Rik
authors.initials: R
authors.lastname: de Greef
authors.forename: Geny M M
authors.initials: GM
authors.lastname: Groothuis
authors.forename: Meindert
authors.initials: M
authors.lastname: Danhof
authors.forename: Johannes H
authors.initials: JH
authors.lastname: Proost
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D001569:Benzodiazepines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D001921:Brain / Q000378:metabolism; D002375:Catalepsy / Q000209:etiology / Q000378:metabolism*; D003198:Computer Simulation; D065127:Dopamine D2 Receptor Antagonists / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007555:Isoxazoles / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D008390:Markov Chains; D008954:Models, Biological; D000077152:Olanzapine; D000068882:Paliperidone Palmitate; D011743:Pyrimidines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D018967:Risperidone / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D012720:Severity of Illness Index
chemical_list: D014150:Antipsychotic Agents; D065127:Dopamine D2 Receptor Antagonists; D007555:Isoxazoles; D011743:Pyrimidines; D017448:Receptors, Dopamine D2; D001569:Benzodiazepines; D018967:Risperidone; D000077152:Olanzapine; D000068882:Paliperidone Palmitate