title: Exploration of optimal dosing regimens of haloperidol, a D2 Antagonist, via modeling and simulation analysis in a D2 receptor occupancy study.
abstract: OBJECTIVE
  To evaluate the potential usage of D(2) receptor occupancy (D2RO) measured by positron emission tomography (PET) in antipsychotic development.
  
  
  METHODS
  In this randomized, parallel group study, eight healthy male volunteers received oral doses of 0.5 (n = 3), 1 (n = 2), or 3 mg (n = 3) of haloperidol once daily for 7 days. PET's were scanned before haloperidol, and on days 8, 12, with serial pharmacokinetic sampling on day 7. Pharmacokinetics and binding potential to D(2) receptor in putamen and caudate nucleus over time were analyzed using NONMEM, and simulations for the profiles of D2RO over time on various regimens of haloperidol were conducted to find the optimal dosing regimens.
  
  
  RESULTS
  One compartment model with a saturable binding compartment, and inhibitory E(max) model in the effect compartment best described the data. Plasma haloperidol concentrations at half-maximal inhibition were 0.791 and 0.650 ng/ml, in putamen and caudate nucleus. Simulation suggested haloperidol 2 mg every 12 h is near the optimal dose.
  
  
  CONCLUSIONS
  This study showed that sparse D2RO measurements in steady state pharmacodynamic design after multiple dosing could reveal the possibility of treatment effect of D(2) antagonist, and could identify the potential optimal doses for later clinical studies by modeling and simulation.
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, Ulsan University College of Medicine, Asan Medical Center, Pungnap-2-dong, Seoul, Republic of Korea.
authors.forename: Hyeong-Seok
authors.initials: HS
authors.lastname: Lim
authors.forename: Su Jin
authors.initials: SJ
authors.lastname: Kim
authors.forename: Yook-Hwan
authors.initials: YH
authors.lastname: Noh
authors.forename: Byung Chul
authors.initials: BC
authors.lastname: Lee
authors.forename: Seok-Joon
authors.initials: SJ
authors.lastname: Jin
authors.forename: Hyun Soo
authors.initials: HS
authors.lastname: Park
authors.forename: Soohyeon
authors.initials: S
authors.lastname: Kim
authors.forename: In-Jin
authors.initials: IJ
authors.lastname: Jang
authors.forename: Sang Eun
authors.initials: SE
authors.lastname: Kim
mesh_terms: D000328:Adult; D014150:Antipsychotic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology*; D065127:Dopamine D2 Receptor Antagonists; D004305:Dose-Response Relationship, Drug; D054796:Drug Dosage Calculations; D006220:Haloperidol / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009010:Monte Carlo Method; D049268:Positron-Emission Tomography; D011485:Protein Binding; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D055815:Young Adult
chemical_list: D014150:Antipsychotic Agents; D065127:Dopamine D2 Receptor Antagonists; D017448:Receptors, Dopamine D2; D006220:Haloperidol