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

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  • معلومة اضافية
    • المصدر:
      Publisher: Springer-Verlag Country of Publication: Germany NLM ID: 7608025 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1432-2072 (Electronic) Linking ISSN: 00333158 NLM ISO Abbreviation: Psychopharmacology (Berl) Subsets: MEDLINE
    • بيانات النشر:
      Original Publication: Berlin, New York, Springer-Verlag.
    • الموضوع:
      Patient Selection*; Alkaloids/*pharmacokinetics ; Antipsychotic Agents/*pharmacokinetics ; Clinical Trials as Topic/*methods ; Raclopride/*pharmacokinetics ; Schizophrenia/*metabolism; Adult ; Alkaloids/administration & dosage ; Alkaloids/blood ; Alkaloids/pharmacology ; Antipsychotic Agents/administration & dosage ; Antipsychotic Agents/blood ; Antipsychotic Agents/pharmacology ; Binding, Competitive ; Carbon Radioisotopes ; Data Interpretation, Statistical ; Dopamine D2 Receptor Antagonists ; Dose-Response Relationship, Drug ; Female ; Half-Life ; Humans ; Male ; Middle Aged ; Models, Biological ; Positron-Emission Tomography ; Protein Binding ; Raclopride/administration & dosage ; Raclopride/blood ; Raclopride/pharmacology ; Radioligand Assay ; Receptor, Serotonin, 5-HT2A/metabolism ; Receptors, Dopamine D2/metabolism ; Schizophrenia/drug therapy ; Young Adult
    • نبذة مختصرة :
      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.
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    • Grant Information:
      G0700995 United Kingdom MRC_ Medical Research Council; MC_U120085814 United Kingdom MRC_ Medical Research Council; MC_U120097115 United Kingdom MRC_ Medical Research Council
    • الرقم المعرف:
      0 (Alkaloids)
      0 (Antipsychotic Agents)
      0 (Carbon Radioisotopes)
      0 (Dopamine D2 Receptor Antagonists)
      0 (Receptor, Serotonin, 5-HT2A)
      0 (Receptors, Dopamine D2)
      0 (YKP 1358)
      430K3SOZ7G (Raclopride)
    • الموضوع:
      Date Created: 20110420 Date Completed: 20120213 Latest Revision: 20220129
    • الموضوع:
      20221213
    • الرقم المعرف:
      10.1007/s00213-011-2306-4
    • الرقم المعرف:
      21503604