Dopamine D2 Occupancy as a Biomarker for Antipsychotics: Quantifying the Relationship with Efficacy and Extrapyramidal Symptoms
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For currently available antipsychotic drugs, blockade of dopamine D2 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 D2 receptor occupancy. Clinical data on pharmacokinetics, D2 receptor occupancy, efficacy, and EPS for several antipsychotics were collected from the public domain. Asenapine data were obtained from in-house trials. D2 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, D2 receptor occupancy, Positive and Negative Syndrome Scale (PANSS) response, and effect on Simpson–Angus Scale (SAS) was then developed. The empirical models describing the D2–PANSS and D2–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 D2 antagonist properties in the treatment of schizophrenia.
KEY WORDSasenapine dopamine D2 receptors mathematical models
The authors thank Dr. Shitij Kapur for his insights and direction during the early development of the models. All authors contributed to the development and writing of the paper and are completely responsible for its scientific content. This study was funded by Merck (Whitehouse Station, NJ, USA). Editorial support was provided by Complete Healthcare Communications, Inc., and funded by Merck (Whitehouse Station, NJ, USA).
Conflicts of interest
Rik de Greef and Joep Schoemaker are employees of Merck Sharp & Dohme (Oss, the Netherlands). John Panagides was an employee of Schering-Plough (formerly Organon), now Merck, at the time the study was conducted. Drs. Maloney and Olsson-Gisleskog were employed by Pharsight, A Certara Company, at the time this research was conducted and have no other interests to report.
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