Martin Johnson1,2, Magdalena Kozielska1,3, Venkatesh Pilla Reddy1,2, An Vermeulen4, Hugh A Barton5, Sarah Grimwood5, Rik de Greef6, Geny M M Groothuis1, Meindert Danhof7, Johannes H Proost8. 1. Department of Pharmacokinetics, Toxicology and Targeting, Groningen Research Institute of Pharmacy, University of Groningen, Antonius Deusinglaan 1, 9713 AV, Groningen, The Netherlands. 2. AstraZeneca, Cambridge, UK. 3. Institute of Engineering, Hanze University of Applied Sciences, Assen, The Netherlands. 4. Clinical Pharmacology & Pharmacometircs, Janssen Research and Development, A Division of Janssen Pharmaceutica NV, Beerse, Belgium. 5. Worldwide Research & Development, Pfizer, Inc., Groton, Connecticut, USA. 6. Quantitative Solutions, Pivot Park, Molenweg 79, 5349 AC, Oss, The Netherlands. 7. Division of Pharmacology, Leiden Academic Center for Drug Research, Leiden, The Netherlands. 8. 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.
Abstract
OBJECTIVES: 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.
OBJECTIVES: 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 humanD2RO of six antipsychotics at clinically relevant doses. RESULTS: Predicted humanD2RO was in good agreement with clinically observed D2RO for five antipsychotics. Models using in vitro information predicted humanD2RO well for most of the compounds evaluated in this analysis. However, humanD2RO 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.
Entities:
Keywords:
PBPK; antipsychotic; dopamine D2 receptor occupancy; schizophrenia; translational research
Authors: A Schotte; P F Janssen; W Gommeren; W H Luyten; P Van Gompel; A S Lesage; K De Loore; J E Leysen Journal: Psychopharmacology (Berl) Date: 1996-03 Impact factor: 4.530
Authors: Meindert Danhof; Elizabeth C M de Lange; Oscar E Della Pasqua; Bart A Ploeger; Rob A Voskuyl Journal: Trends Pharmacol Sci Date: 2008-03-18 Impact factor: 14.819
Authors: Martin Johnson; Magdalena Kozielska; Venkatesh Pilla Reddy; An Vermeulen; Cheryl Li; Sarah Grimwood; Rik de Greef; Geny M M Groothuis; Meindert Danhof; Johannes H Proost Journal: Pharm Res Date: 2011-06-07 Impact factor: 4.200
Authors: Yumi Yamamoto; Pyry A Välitalo; Dirk-Jan van den Berg; Robin Hartman; Willem van den Brink; Yin Cheong Wong; Dymphy R Huntjens; Johannes H Proost; An Vermeulen; Walter Krauwinkel; Suruchi Bakshi; Vincent Aranzana-Climent; Sandrine Marchand; Claire Dahyot-Fizelier; William Couet; Meindert Danhof; Johan G C van Hasselt; Elizabeth C M de Lange Journal: Pharm Res Date: 2016-11-18 Impact factor: 4.200
Authors: Amit Taneja; An Vermeulen; Dymphy R H Huntjens; Meindert Danhof; Elizabeth C M De Lange; Johannes H Proost Journal: Pharmacol Res Perspect Date: 2017-12