title: Dopamine D2 occupancy as a biomarker for antipsychotics: quantifying the relationship with efficacy and extrapyramidal symptoms.
abstract: For currently available antipsychotic drugs, blockade of dopamine D(2) receptors is a critical component for achieving antipsychotic efficacy, but it is also a driving factor in the development of extrapyramidal symptoms (EPS). To inform the clinical development of asenapine, generic mathematical models have been developed for predicting antipsychotic efficacy and EPS tolerability based on D(2) receptor occupancy. Clinical data on pharmacokinetics, D(2) receptor occupancy, efficacy, and EPS for several antipsychotics were collected from the public domain. Asenapine data were obtained from in-house trials. D(2) receptor occupancy data were restricted to published positron emission tomography studies that included blood sampling for pharmacokinetics. Clinical efficacy data were restricted to group mean endpoint data from short-term placebo-controlled trials, whereas EPS evaluation also included some non-placebo-controlled trials. A generally applicable model connecting antipsychotic dose, pharmacokinetics, D(2) receptor occupancy, Positive and Negative Syndrome Scale (PANSS) response, and effect on Simpson-Angus Scale (SAS) was then developed. The empirical models describing the D(2)-PANSS and D(2)-SAS relationships were used successfully to aid dose selection for asenapine phase II and III trials. A broader use can be envisaged as a dose selection tool for new antipsychotics with D(2) antagonist properties in the treatment of schizophrenia.
authors.affiliation: Merck Research Laboratories, Merck Sharp & Dohme, PO Box 20, 5340 BH, Oss, the Netherlands. rik.degreef@merck.com
authors.forename: Rik
authors.initials: R
authors.lastname: de Greef
authors.forename: Alan
authors.initials: A
authors.lastname: Maloney
authors.forename: Per
authors.initials: P
authors.lastname: Olsson-Gisleskog
authors.forename: Joep
authors.initials: J
authors.lastname: Schoemaker
authors.forename: John
authors.initials: J
authors.lastname: Panagides
mesh_terms: D000465:Algorithms; D014150:Antipsychotic Agents / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D001480:Basal Ganglia Diseases / Q000139:chemically induced* / Q000503:physiopathology; D001682:Biological Availability; D015415:Biomarkers; D003198:Computer Simulation; D003986:Dibenzocycloheptenes; D004305:Dose-Response Relationship, Drug; D023381:Endpoint Determination; D006576:Heterocyclic Compounds, 4 or More Rings / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D006801:Humans; D015233:Models, Statistical; D049268:Positron-Emission Tomography; D011569:Psychiatric Status Rating Scales; D017448:Receptors, Dopamine D2 / Q000187:drug effects* / Q000378:metabolism; D012559:Schizophrenia / Q000150:complications / Q000188:drug therapy / Q000503:physiopathology; D012565:Schizophrenic Psychology; D015899:Tomography, Emission-Computed, Single-Photon
chemical_list: D014150:Antipsychotic Agents; D015415:Biomarkers; D003986:Dibenzocycloheptenes; D006576:Heterocyclic Compounds, 4 or More Rings; D017448:Receptors, Dopamine D2; C522667:asenapine