The use of healthy volunteers instead of patients to inform drug dosing studies: a [¹¹C]raclopride PET study

Psychopharmacology (Berl). 2011 Oct;217(4):515-23. doi: 10.1007/s00213-011-2306-4. Epub 2011 Apr 19.

Abstract

Rationale: 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.

Objectives: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Alkaloids / administration & dosage
  • Alkaloids / blood
  • Alkaloids / pharmacokinetics*
  • Alkaloids / pharmacology
  • Antipsychotic Agents / administration & dosage
  • Antipsychotic Agents / blood
  • Antipsychotic Agents / pharmacokinetics*
  • Antipsychotic Agents / pharmacology
  • Binding, Competitive
  • Carbon Radioisotopes
  • Clinical Trials as Topic / methods*
  • Data Interpretation, Statistical
  • Dopamine D2 Receptor Antagonists
  • Dose-Response Relationship, Drug
  • Female
  • Half-Life
  • Humans
  • Male
  • Middle Aged
  • Models, Biological
  • Patient Selection*
  • Positron-Emission Tomography
  • Protein Binding
  • Raclopride / administration & dosage
  • Raclopride / blood
  • Raclopride / pharmacokinetics*
  • Raclopride / pharmacology
  • Radioligand Assay
  • Receptor, Serotonin, 5-HT2A / metabolism
  • Receptors, Dopamine D2 / metabolism
  • Schizophrenia / drug therapy
  • Schizophrenia / metabolism*
  • Young Adult

Substances

  • Alkaloids
  • Antipsychotic Agents
  • Carbon Radioisotopes
  • Dopamine D2 Receptor Antagonists
  • Receptor, Serotonin, 5-HT2A
  • Receptors, Dopamine D2
  • YKP 1358
  • Raclopride