title: Human microdose evaluation of the novel EP1 receptor antagonist GSK269984A.
abstract: OBJECTIVE
  The primary objective was to evaluate the pharmacokinetics (PK) of the novel EP(1) antagonist GSK269984A in human volunteers after a single oral and intravenous (i.v.) microdose (100 µg).
  
  
  METHODS
  GSK269984A was administered to two groups of healthy human volunteers as a single oral (n= 5) or i.v. (n= 5) microdose (100 µg). Blood samples were collected for up to 24 h and the parent drug concentrations were measured in separated plasma using a validated high pressure liquid chromatography-tandem mass spectrometry method following solid phase extraction.
  
  
  RESULTS
  Following the i.v. microdose, the geometric mean values for clearance (CL), steady-state volume of distribution (V(ss) ) and terminal elimination half-life (t(1/2) ) of GSK269984A were 9.8 l h(-1) , 62.8 l and 8.2 h. C(max) and AUC(0,∞) were 3.2 ng ml(-1) and 10.2 ng ml(-1)  h, respectively; the corresponding oral parameters were 1.8 ng ml(-1) and 9.8 ng ml(-1)  h, respectively. Absolute oral bioavailability was estimated to be 95%. These data were inconsistent with predictions of human PK based on allometric scaling of in vivo PK data from three pre-clinical species (rat, dog and monkey).
  
  
  CONCLUSIONS
  For drug development programmes characterized by inconsistencies between pre-clinical in vitro metabolic and in vivo PK data, and where uncertainty exists with respect to allometric predictions of the human PK profile, these data support the early application of a human microdose study to facilitate the selection of compounds for further clinical development.
authors.affiliation: Neurology Discovery Medicine, GlaxoSmithKline R&D, Harlow, UK. thor.x.ostenfeld@gsk.com
authors.forename: Thor
authors.initials: T
authors.lastname: Ostenfeld
authors.forename: Claire
authors.initials: C
authors.lastname: Beaumont
authors.forename: Jonathan
authors.initials: J
authors.lastname: Bullman
authors.forename: Maria
authors.initials: M
authors.lastname: Beaumont
authors.forename: Phillip
authors.initials: P
authors.lastname: Jeffrey
mesh_terms: D061605:Administration, Intravenous; D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000818:Animals; D001682:Biological Availability; D002853:Chromatography, Liquid / Q000379:methods; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D054796:Drug Dosage Calculations; D004341:Drug Evaluation / Q000379:methods*; D006207:Half-Life; D000882:Haplorhini; D006801:Humans; D008297:Male; D008875:Middle Aged; D023421:Models, Animal; D009539:Nicotinic Acids / Q000737:chemistry / Q000493:pharmacokinetics*; D051381:Rats; D018078:Receptors, Prostaglandin E / Q000037:antagonists & inhibitors*; D058306:Receptors, Prostaglandin E, EP1 Subtype / Q000037:antagonists & inhibitors*; D053719:Tandem Mass Spectrometry / Q000379:methods; D055815:Young Adult
chemical_list: D009539:Nicotinic Acids; D018078:Receptors, Prostaglandin E; D058306:Receptors, Prostaglandin E, EP1 Subtype; C542999:sodium 6-((5-chloro-2-(((4-chloro-2-fluorophenyl)methyl)oxy)phenyl)methyl)-2-pyridinecarboxylate