Human microdose evaluation of the novel EP1 receptor antagonist GSK269984A

Br J Clin Pharmacol. 2012 Dec;74(6):1033-44. doi: 10.1111/j.1365-2125.2012.04296.x.


Aim: 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).

Method: 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).

Conclusion: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Intravenous
  • Administration, Oral
  • Adolescent
  • Adult
  • Animals
  • Biological Availability
  • Chromatography, Liquid / methods
  • Dogs
  • Dose-Response Relationship, Drug
  • Drug Dosage Calculations
  • Drug Evaluation / methods*
  • Half-Life
  • Haplorhini
  • Humans
  • Male
  • Middle Aged
  • Models, Animal
  • Nicotinic Acids / chemistry
  • Nicotinic Acids / pharmacokinetics*
  • Rats
  • Receptors, Prostaglandin E / antagonists & inhibitors*
  • Receptors, Prostaglandin E, EP1 Subtype / antagonists & inhibitors*
  • Tandem Mass Spectrometry / methods
  • Young Adult


  • Nicotinic Acids
  • Receptors, Prostaglandin E
  • Receptors, Prostaglandin E, EP1 Subtype
  • sodium 6-((5-chloro-2-(((4-chloro-2-fluorophenyl)methyl)oxy)phenyl)methyl)-2-pyridinecarboxylate