title: Mechanism-based pharmacokinetic-pharmacodynamic modeling of the dopamine D2 receptor occupancy of olanzapine in rats.
abstract: OBJECTIVE
  A mechanism-based PK-PD model was developed to predict the time course of dopamine D(2) receptor occupancy (D(2)RO) in rat striatum following administration of olanzapine, an atypical antipsychotic drug.
  
  
  METHODS
  A population approach was utilized to quantify both the pharmacokinetics and pharmacodynamics of olanzapine in rats using the exposure (plasma and brain concentration) and D(2)RO profile obtained experimentally at various doses (0.01-40 mg/kg) administered by different routes. A two-compartment pharmacokinetic model was used to describe the plasma pharmacokinetic profile. A hybrid physiology- and mechanism-based model was developed to characterize the D(2) receptor binding in the striatum and was fitted sequentially to the data. The parameters were estimated using nonlinear mixed-effects modeling .
  
  
  RESULTS
  Plasma, brain concentration profiles and time course of D(2)RO were well described by the model; validity of the proposed model is supported by good agreement between estimated association and dissociation rate constants and in vitro values from literature.
  
  
  CONCLUSIONS
  This model includes both receptor binding kinetics and pharmacokinetics as the basis for the prediction of the D(2)RO in rats. Moreover, this modeling framework can be applied to scale the in vitro and preclinical information to clinical receptor occupancy.
authors.affiliation: Department of Pharmacokinetics, Toxicology and Targeting, University of Groningen, Antonius Deusinglaan 1, 9713 AV, Groningen, 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: Cheryl
authors.initials: C
authors.lastname: Li
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 / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D001569:Benzodiazepines / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D018492:Dopamine Antagonists / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D065127:Dopamine D2 Receptor Antagonists; D007700:Kinetics; D008954:Models, Biological; D017711:Nonlinear Dynamics; D000077152:Olanzapine; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D017448:Receptors, Dopamine D2 / Q000378:metabolism*
chemical_list: D014150:Antipsychotic Agents; D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; D017448:Receptors, Dopamine D2; D001569:Benzodiazepines; D000077152:Olanzapine