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.
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.
Authors: J L Stock; K Shinjo; J Burkhardt; M Roach; K Taniguchi; T Ishikawa; H S Kim; P J Flannery; T M Coffman; J D McNeish; L P Audoly Journal: J Clin Invest Date: 2001-02 Impact factor: 14.808
Authors: T Minami; H Nakano; T Kobayashi; Y Sugimoto; F Ushikubi; A Ichikawa; S Narumiya; S Ito Journal: Br J Pharmacol Date: 2001-06 Impact factor: 8.739
Authors: Catherine E Trebino; Jeffrey L Stock; Colleen P Gibbons; Brian M Naiman; Timothy S Wachtmann; John P Umland; Karamjeet Pandher; Jean-Martin Lapointe; Sipra Saha; Marsha L Roach; Demetrius Carter; Nathalie A Thomas; Becky A Durtschi; John D McNeish; John E Hambor; Per-Johan Jakobsson; Thomas J Carty; Jose R Perez; Laurent P Audoly Journal: Proc Natl Acad Sci U S A Date: 2003-06-30 Impact factor: 11.205