Pharmacokinetics, pharmacodynamics and safety of single, oral doses of GSK1278863, a novel HIF-prolyl hydroxylase inhibitor, in healthy Japanese and Caucasian subjects

• Published in: Drug metabolism and pharmacokinetics Vol. 30; no. 6; pp. 410 - 418
• Main Authors: Hara, Katsutoshi, Takahashi, Naoki, Wakamatsu, Akira, Caltabiano, Stephen
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.12.2015
• Subjects: Administration, Oral; Adult; Anemia; Area Under Curve; Asian Continental Ancestry Group; Barbiturates - administration & dosage; Barbiturates - adverse effects; Barbiturates - blood; Barbiturates - pharmacokinetics; Body Weight - ethnology; Dose-Response Relationship, Drug; Enzyme Inhibitors - administration & dosage; Enzyme Inhibitors - adverse effects; Enzyme Inhibitors - blood; Enzyme Inhibitors - pharmacokinetics; Erythropoietin; Erythropoietin - blood; European Continental Ancestry Group; Glycine - administration & dosage; Glycine - adverse effects; Glycine - analogs & derivatives; Glycine - blood; Glycine - pharmacokinetics; GSK1278863; Half-Life; Healthy Volunteers; Humans; Hypoxia-inducible factor; Hypoxia-Inducible Factor-Proline Dioxygenases - antagonists & inhibitors; Hypoxia-Inducible Factor-Proline Dioxygenases - metabolism; Japan; Male; Metabolic Clearance Rate; Pharmacodynamics; Pharmacokinetics; PK–PD; Prolyl hydroxylase inhibitor; Reticulocytes; Reticulocytes - drug effects; Reticulocytes - metabolism; Single-Blind Method; Vascular Endothelial Growth Factor A - blood; Young Adult; Japan; Prolyl hydroxylase inhibitor; Pharmacodynamics; Erythropoietin; Anemia; Hypoxia-inducible factor; Reticulocytes; Pharmacokinetics; PK–PD; GSK1278863
• ISSN: 1347-4367; 1880-0920; 1880-0920
• DOI: 10.1016/j.dmpk.2015.08.004

This study was performed to evaluate the pharmacokinetics (PK), pharmacodynamics (PD) and safety of GSK1278863, a novel prolyl hydroxylase inhibitor, following a single oral administration of GSK1278863 from 10 to 100 mg or placebo in Japanese (n = 19), and 10, 25 and 100 mg in Caucasians (n = 14). Dose-proportional increases were observed in AUCinf of GSK1278863 in both ethnic groups, with a 1.3–1.5-fold higher exposure seen in Japanese relative to Caucasians for all doses. This difference in exposure can be mainly explained by the observed differences in body weights between the two groups. Statistically significant increases in erythropoietin (EPO), vascular endothelial growth factor (VEGF) and reticulocyte counts were observed in Japanese subjects after the 50 and 100 mg dose as compared to placebo. In Caucasians, similar to Japanese, EPO and VEGF levels were observed to be increased in response to the 100 mg dose. Drug-related adverse events, including headache and abdominal pain were reported in 3 Japanese subjects, while headache was reported in 3 Caucasians. In conclusion, GSK1278863 was well tolerated, with dose-proportional increases in exposure observed in both groups. There was no evidence of ethnic differences between Japanese and Caucasian with regard to PK or PD.