title: The use of healthy volunteers instead of patients to inform drug dosing studies: a [¹¹C]raclopride PET study.
abstract: BACKGROUND
  Receptor occupancy study has been performed to evaluate pharmacokinetic profiles in new antipsychotic drug development. While these findings highlight the value of positron emission tomography (PET) for dose-finding study, what is unclear is if it is necessary to conduct these studies in patients with schizophrenia or whether studies in healthy volunteers are adequate.
  
  
  OBJECTIVE
  To determine if it is necessary to conduct dopamine receptor occupancy studies in patients with schizophrenia or whether studies in healthy volunteers are adequate for dose-finding study, we compared the concentration-occupancy relationship in terms of EC(50) between patients and healthy volunteers.
  
  
  METHODS
  Ten healthy volunteers and eight patients with schizophrenia participated in the study. We measured dopamine receptor occupancy using [(11)C]raclopride PET and plasma concentration of YKP1358, a novel antipsychotic drug under clinical development, at a number of time points after the administration of YKP1358. Pharmacokinetic data including area under the plasma concentration versus time curve, elimination half-life, maximum observed plasma concentration, and the time to reach the maximum observed plasma concentration were obtained. We explored the relationship between plasma concentration and dopamine D(2) receptor occupancy using E (max) model and calculated EC(50).
  
  
  RESULTS
  The elimination half-life was longer in healthy volunteers than in patients. Other pharmacokinetic parameters were not significantly different between two groups. The EC(50) was 7.6 ng/ml (95% confidence interval (CI) 6.2-9.0) in healthy volunteers and 8.6 (95% CI 7.4-9.9) in patients.
  
  
  CONCLUSIONS
  The antipsychotic concentration-occupancy relationship in patients can be estimated from the EC(50) data of healthy volunteers.
authors.affiliation: Department of Psychiatry, Seoul National University College of Medicine, 28 Yeongon-dong, Chongno-gu, Seoul 110-744, South Korea.
authors.forename: Euitae
authors.initials: E
authors.lastname: Kim
authors.forename: Oliver D
authors.initials: OD
authors.lastname: Howes
authors.forename: Bo-Hyung
authors.initials: BH
authors.lastname: Kim
authors.forename: Kyung-Sang
authors.initials: KS
authors.lastname: Yu
authors.forename: Jae Min
authors.initials: JM
authors.lastname: Jeong
authors.forename: Jae Sung
authors.initials: JS
authors.lastname: Lee
authors.forename: Su Jin
authors.initials: SJ
authors.lastname: Kim
authors.forename: In-Jin
authors.initials: IJ
authors.lastname: Jang
authors.forename: Jung Shin
authors.initials: JS
authors.lastname: Park
authors.forename: Yong Gil
authors.initials: YG
authors.lastname: Kim
authors.forename: Sang-Goo
authors.initials: SG
authors.lastname: Shin
authors.forename: Federico E
authors.initials: FE
authors.lastname: Turkheimer
authors.forename: Shitij
authors.initials: S
authors.lastname: Kapur
authors.forename: Jun Soo
authors.initials: JS
authors.lastname: Kwon
mesh_terms: D000328:Adult; D000470:Alkaloids / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D001667:Binding, Competitive; D002250:Carbon Radioisotopes; D002986:Clinical Trials as Topic / Q000379:methods*; D003627:Data Interpretation, Statistical; D065127:Dopamine D2 Receptor Antagonists; D004305:Dose-Response Relationship, Drug; D005260:Female; D006207:Half-Life; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D018579:Patient Selection; D049268:Positron-Emission Tomography; D011485:Protein Binding; D020891:Raclopride / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D011869:Radioligand Assay; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D012559:Schizophrenia / Q000188:drug therapy / Q000378:metabolism*; D055815:Young Adult
chemical_list: D000470:Alkaloids; D014150:Antipsychotic Agents; D002250:Carbon Radioisotopes; D065127:Dopamine D2 Receptor Antagonists; D044402:Receptor, Serotonin, 5-HT2A; D017448:Receptors, Dopamine D2; C518965:YKP 1358; D020891:Raclopride