title: Translational Modeling in Schizophrenia: Predicting Human Dopamine D2 Receptor Occupancy.
abstract: OBJECTIVE
  To assess the ability of a previously developed hybrid physiology-based pharmacokinetic-pharmacodynamic (PBPKPD) model in rats to predict the dopamine D2 receptor occupancy (D2RO) in human striatum following administration of antipsychotic drugs.
  
  
  METHODS
  A hybrid PBPKPD model, previously developed using information on plasma concentrations, brain exposure and D2RO in rats, was used as the basis for the prediction of D2RO in human. The rat pharmacokinetic and brain physiology parameters were substituted with human population pharmacokinetic parameters and human physiological information. To predict the passive transport across the human blood-brain barrier, apparent permeability values were scaled based on rat and human brain endothelial surface area. Active efflux clearance in brain was scaled from rat to human using both human brain endothelial surface area and MDR1 expression. Binding constants at the D2 receptor were scaled based on the differences between in vitro and in vivo systems of the same species. The predictive power of this physiology-based approach was determined by comparing the D2RO predictions with the observed human D2RO of six antipsychotics at clinically relevant doses.
  
  
  RESULTS
  Predicted human D2RO was in good agreement with clinically observed D2RO for five antipsychotics. Models using in vitro information predicted human D2RO well for most of the compounds evaluated in this analysis. However, human D2RO was under-predicted for haloperidol.
  
  
  CONCLUSIONS
  The rat hybrid PBPKPD model structure, integrated with in vitro information and human pharmacokinetic and physiological information, constitutes a scientific basis to predict the time course of D2RO in man.
authors.affiliation: Department of Pharmacokinetics, Toxicology and Targeting, Groningen Research Institute of Pharmacy, University of Groningen, Antonius Deusinglaan 1, 9713 AV, Groningen, The Netherlands.|AstraZeneca, Cambridge, UK.
authors.forename: Martin
authors.initials: M
authors.lastname: Johnson
authors.affiliation: Department of Pharmacokinetics, Toxicology and Targeting, Groningen Research Institute of Pharmacy, University of Groningen, Antonius Deusinglaan 1, 9713 AV, Groningen, The Netherlands.|Institute of Engineering, Hanze University of Applied Sciences, Assen, The Netherlands.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Kozielska
authors.affiliation: Department of Pharmacokinetics, Toxicology and Targeting, Groningen Research Institute of Pharmacy, University of Groningen, Antonius Deusinglaan 1, 9713 AV, Groningen, The Netherlands.|AstraZeneca, Cambridge, UK.
authors.forename: Venkatesh
authors.initials: V
authors.lastname: Pilla Reddy
authors.affiliation: Clinical Pharmacology & Pharmacometircs, Janssen Research and Development, A Division of Janssen Pharmaceutica NV, Beerse, Belgium.
authors.forename: An
authors.initials: A
authors.lastname: Vermeulen
authors.affiliation: Worldwide Research & Development, Pfizer, Inc., Groton, Connecticut, USA.
authors.forename: Hugh A
authors.initials: HA
authors.lastname: Barton
authors.affiliation: Worldwide Research & Development, Pfizer, Inc., Groton, Connecticut, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Grimwood
authors.affiliation: Quantitative Solutions, Pivot Park, Molenweg 79, 5349 AC, Oss, The Netherlands.
authors.forename: Rik
authors.initials: R
authors.lastname: de Greef
authors.affiliation: Department of Pharmacokinetics, Toxicology and Targeting, Groningen Research Institute of Pharmacy, University of Groningen, Antonius Deusinglaan 1, 9713 AV, Groningen, The Netherlands.
authors.forename: Geny M M
authors.initials: GM
authors.lastname: Groothuis
authors.affiliation: Division of Pharmacology, Leiden Academic Center for Drug Research, Leiden, The Netherlands.
authors.forename: Meindert
authors.initials: M
authors.lastname: Danhof
authors.affiliation: Department of Pharmacokinetics, Toxicology and Targeting, Groningen Research Institute of Pharmacy, University of Groningen, Antonius Deusinglaan 1, 9713 AV, Groningen, The Netherlands. j.h.proost@rug.nl.
authors.forename: Johannes H
authors.initials: JH
authors.lastname: Proost
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism*; D065127:Dopamine D2 Receptor Antagonists / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D008954:Models, Biological; D051381:Rats; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D012559:Schizophrenia / Q000188:drug therapy* / Q000378:metabolism
chemical_list: D014150:Antipsychotic Agents; C581293:DRD2 protein, human; D065127:Dopamine D2 Receptor Antagonists; D017448:Receptors, Dopamine D2
keywords: PBPK; antipsychotic; dopamine D2 receptor occupancy; schizophrenia; translational research