title: A pharmacokinetic PET study of NK₁ receptor occupancy.
abstract: OBJECTIVE
  There is growing recognition of the importance of integrating drug occupancy data acquired by positron emission tomography (PET) with the plasma pharmacokinetics of the drug, in order to establish proper dose selection in subsequent clinical trials. Here we present a study in human subjects of the occupancy of NK(1) receptors achieved following different doses of casopitant, a selective NK(1) antagonist.
  
  
  METHODS
  Two PET scans were carried out in each of eight human subjects, with the PET radioligand [(11)C]GR205171, a high-affinity and selective NK(1) receptor antagonist. The first scan was under baseline conditions and the second 24 h after a single oral dose of casopitant (2-120 mg). Arterial blood was collected throughout the scans for determination of plasma and whole blood input functions. Venous blood samples were taken prior to and following oral dosing up to 24 h for a pharmacokinetic study of casopitant concentration in plasma.
  
  
  RESULTS
  It was first necessary to establish a suitable kinetic model for the estimation of [(11)C]GR205171 NK(1) receptor binding parameters in human brain tissue. A three-tissue compartment model with simultaneous estimation of multiple regions sharing common variables across regions was found suitable for the analysis. Because of the injected cold mass of the tracer and the high affinity of [(11)C]GR205171 a correction for tracer occupancy effects was also incorporated into the analysis. We then developed a pharmacokinetic-receptor occupancy (PK-RO) model of the relationship between casopitant plasma concentrations and receptor binding, using a population approach.
  
  
  CONCLUSIONS
  These results indicate that after chronic dosing, casopitant can achieve a degree of NK(1) receptor occupancy higher than those that have previously been tested in studies of clinical depression.
authors: GlaxoSmithKline, Clinical Pharmacology Modeling & Simulation, Stockley Park, UK. Stefano.6.zamuner@gsk.com
authors: Stefano
authors: S
authors: Zamuner
authors: Eugenii A
authors: EA
authors: Rabiner
authors: Sofia A
authors: SA
authors: Fernandes
authors: Massimo
authors: M
authors: Bani
authors: Roger N
authors: RN
authors: Gunn
authors: Roberto
authors: R
authors: Gomeni
authors: Emilangelo
authors: E
authors: Ratti
authors: Vincent J
authors: VJ
authors: Cunningham
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000932:Antiemetics / Q000494:pharmacology; D002247:Carbon Isotopes / Q000494:pharmacology; D003863:Depression / Q000188:drug therapy; D006801:Humans; D007700:Kinetics; D008297:Male; D008875:Middle Aged; D010879:Piperazines / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D049268:Positron-Emission Tomography / Q000379:methods*; D018040:Receptors, Neurokinin-1 / Q000378:metabolism*; D013777:Tetrazoles / Q000494:pharmacology; D013997:Time Factors; D014508:Urea
chemical_list: D000932:Antiemetics; D002247:Carbon Isotopes; D010879:Piperazines; D010880:Piperidines; D018040:Receptors, Neurokinin-1; D013777:Tetrazoles; C531951:casopitant; D014508:Urea; C103207:vofopitant