title: Population pharmacokinetics of JNJ-37822681, a selective fast-dissociating dopamine D₂-receptor antagonist, in healthy subjects and subjects with schizophrenia and dose selection based on simulated D₂-receptor occupancy.
abstract: OBJECTIVE
  JNJ-37822681 is a selective, fast-dissociating dopamine D2-receptor antagonist currently in development as a candidate antipsychotic. The aim of the analyses was to develop a population pharmacokinetic model to describe the pharmacokinetics of JNJ-37822681 in healthy subjects and patients with schizophrenia and to identify covariates of interest. The model was then used to simulate D2-receptor occupancy in support of dose selection for subsequent studies.
  
  
  METHODS
  Data were obtained from 378 subjects enrolled in three phase I and two phase II studies. Nonlinear mixed effects modeling of pooled data was conducted using NONMEM(®) to estimate population pharmacokinetic parameters and the effect of covariates on these parameters. The model was evaluated on a subset of data that was not used for model building and was subsequently used to simulate steady-state exposure for each subject in the phase IIb study. Striatal D2-receptor occupancy was predicted using simulated exposure combined with pharmacodynamic parameters from a sigmoid maximum effect model established from previous [(11)C]raclopride positron emission tomography studies.
  
  
  RESULTS
  A two-compartment disposition model with zero-order input in a depot compartment followed by first-order absorption into and first-order elimination from the central compartment combined with a transit compartment provided the best fit to the data. Significant covariates were sex and bioavailability on apparent clearance and food intake on the absorption rate constant. Clearance was 11 % higher in females compared with males. The model passed external evaluation. The estimated pharmacokinetic parameters for the phase IIb study were similar to those observed in the phase IIa study. D2-receptor occupancy was predicted to be in the 65-80 % range at 10 mg twice daily and partially or fully reaching the 80 % threshold at doses of 20 and 30 mg twice daily.
  
  
  CONCLUSIONS
  The population pharmacokinetic model of JNJ-37822681 successfully described the pharmacokinetics of JNJ-37822681 and allowed the reliable determination of individual exposure parameters in a phase IIb study. It was concluded that 5 or 7.5 mg twice daily would likely be minimal- or no-effect doses, whereas 10 mg twice daily was expected to provide an optimal balance of efficacy and tolerability.
authors.affiliation: Model Based Drug Development, Janssen Research and Development, A Division of Janssen Pharmaceutica NV, Turnhoutseweg 30, 2340, Beerse, Belgium, ehoeben@its.jnj.com.
authors.forename: Eef
authors.initials: E
authors.lastname: Hoeben
authors.forename: Martine
authors.initials: M
authors.lastname: Neyens
authors.forename: Erik
authors.initials: E
authors.lastname: Mannaert
authors.forename: Mark
authors.initials: M
authors.lastname: Schmidt
authors.forename: An
authors.initials: A
authors.lastname: Vermeulen
mesh_terms: D000328:Adult; D000368:Aged; D014150:Antipsychotic Agents / Q000493:pharmacokinetics*; D065127:Dopamine D2 Receptor Antagonists; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D010880:Piperidines / Q000097:blood / Q000493:pharmacokinetics*; D011724:Pyridazines / Q000097:blood / Q000493:pharmacokinetics*; D017448:Receptors, Dopamine D2 / Q000097:blood / Q000378:metabolism; D012559:Schizophrenia / Q000378:metabolism*; D055815:Young Adult
chemical_list: D014150:Antipsychotic Agents; 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