Predicting Dopamine D2 Receptor Occupancy in humans using a physiology-based approach
Martin Johnson* (1), Magdalena Kozielska (1), Venkatesh Pilla Reddy (1), An Vermeulen (2), Hugh A.Barton (3), Sarah Grimwood (3), Rik de Greef (4), Geny M.M. Groothuis (1), Meindert Danhof (5), & Johannes H. Proost (1)
(1) Department of Pharmacokinetics, Toxicology & Targeting, University of Groningen, The Netherlands; (2) Advanced PK-PD Modeling & Simulation, Janssen Research & Development, Beerse, Belgium; (3) Worldwide Research & Development, Pfizer, Inc., Groton, CT, USA; (4) Pharmacokinetics, Pharmacodynamics & Pharmacometrics (P3), Merck Sharp & Dohme, Oss, The Netherlands; (5) Division of Pharmacology, Leiden/Amsterdam Center For Drug Research, Leiden, The Netherlands.
Objectives: A hybrid physiology-based pharmacokinetic and pharmacodynamic model (PBPKPD) was used to predict the time course of dopamine receptor occupancy (D2RO) in human striatum following the administration of antipsychotic (AP) drugs, using in vitro and in silico information.
Methods: A hybrid PBPKPD model to predict the D2RO in human was developed using plasma, brain exposure and D2RO information from rats. This PBPKPD model consisted of classical plasma compartments and four physiology-based brain compartments: brain-vascular, brain-extravascular, striatum free drug, and striatum bound drug. The drug distribution from the plasma compartment to the brain-vascular compartment was assumed to be determined by cerebral blood flow. The unbound drug in this vascular compartment crosses the blood-brain barrier into the brain-extravascular compartment, then to striatum where it can reversibly bind to the dopamine receptor complex. This rat brain physiology-based model structure was integrated with available population pharmacokinetic parameters, in vitro, in silico and human physiological information to predict the human D2RO of haloperidol, risperidone and paliperidone at clinically relevant doses. Permeability surface area product (PS) was obtained using in silico calculations and used to predict the transport of drug across the human blood brain barrier(1). Active efflux clearance in brain was scaled from the model estimates obtained from the rat PBPKPD model. Berkeley Madonna was used to make these predictions. The predictive power of this physiology-based approach was determined by comparing the simulations with the observed human D2RO(2;3).
Results: The model-predicted human D2RO are in close agreement with the clinically observed D2RO at relevant doses for risperidone and paliperidone. However, it was underpredicted for haloperidol.
Conclusion: The rat hybrid PBPKPD model structure as integrated with in silico, in vitro and humanphysiological information was able to predict the time course of D2RO in human for risperidone and paliperidone well and less so for haloperidol.
 Summerfield SG, Read K, Begley DJ, Obradovic T, Hidalgo IJ, Coggon S, et al. Central nervous system drug disposition: the relationship between in situ brain permeability and brain free fraction. J Pharmacol Exp Ther 2007 Jul;322(1):205-13.
 Catafau AM, Penengo MM, Nucci G, Bullich S, Corripio I, Parellada E, et al. Pharmacokinetics and time-course of D(2) receptor occupancy induced by atypical antipsychotics in stabilized schizophrenic patients. J Psychopharmacol 2008 Nov;22(8):882-94.
 Nucci G, Gomeni R, Poggesi I. Model-based approaches to increase efficiency of drug development in schizophrenia: a can't miss opportunity. Expert Opinion on Drug Discovery 2010;5(9):907.