title: D₂-receptor occupancy measurement of JNJ-37822681, a novel fast off-rate D₂-receptor antagonist, in healthy subjects using positron emission tomography: single dose versus steady state and dose selection.
abstract: BACKGROUND
  JNJ-37822681 is a highly selective, fast dissociating dopamine D₂-receptor antagonist being developed for the treatment of schizophrenia. A single dose [¹¹C]raclopride positron emission tomography (PET) imaging study had yielded an estimated clinical dose range. Receptor occupancy at steady state was explored to test the validity of the single-dose estimates during chronic treatment.
  
  
  OBJECTIVE
  The aims of this study are to characterize single and multiple dose pharmacokinetics and obtain striatal D₂-receptor occupancies to predict doses for efficacy studies and assess the safety and tolerability of JNJ-37822681.
  
  
  METHODS
  An open-label single- and multiple-dose study with 10 mg JNJ-37822681 (twice daily for 13 doses) was performed in 12 healthy men. Twenty [¹¹C]raclopride PET scans (up to 60 h after the last dose) from 11 subjects were used to estimate D₂-receptor occupancy. A direct effect O (max) model was applied to explore the relationship between JNJ-37822681 plasma concentration and striatal D₂-receptor occupancy.
  
  
  RESULTS
  Steady state was reached after 4-5 days of twice daily dosing. JNJ-37822681 plasma concentrations of 3.17 to 63.0 ng/mL resulted in D₂ occupancies of 0 % to 62 %. The concentration leading to 50 % occupancy was 18.5 ng/mL (coefficient of variation 3.9 %) after single dose and 26.0 ng/mL (8.2 %) at steady state. JNJ-37822681 was well tolerated.
  
  
  CONCLUSIONS
  Receptor occupancy after single dose and at steady state differed for JNJ-37822681 and the robustness of the estimates at steady state will be tested in phase 2 studies. Dose predictions indicated that 10, 20, and 30 mg JNJ-37822681 twice daily could be suitable for these studies.
authors: Experimental Medicine, Janssen Research and Development, Janssen Pharmaceutica NV, Beerse, Belgium.
authors: Mark E
authors: ME
authors: Schmidt
authors: Peter
authors: P
authors: de Boer
authors: Randolph
authors: R
authors: Andrews
authors: Martine
authors: M
authors: Neyens
authors: Stefaan
authors: S
authors: Rossenu
authors: Demiana
authors: D
authors: William Falteos
authors: Erik
authors: E
authors: Mannaert
mesh_terms: D000328:Adult; D018492:Dopamine Antagonists / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics; D065127:Dopamine D2 Receptor Antagonists; D004334:Drug Administration Schedule; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D010880:Piperidines / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics; D049268:Positron-Emission Tomography / Q000379:methods*; D011724:Pyridazines / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics; D020891:Raclopride / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D013997:Time Factors; D055815:Young Adult
chemical_list: D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; C576398:N-(1-(3,4-difluorobenzyl)piperidin-4-yl)-6-(trifluoromethyl)pyridazin-3-amine; D010880:Piperidines; D011724:Pyridazines; D017448:Receptors, Dopamine D2; D020891:Raclopride