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

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

  • Drug Metab Pharmacokinet. 2015 Dec;30(6):410-8. doi: 10.1016/j.dmpk.2015.08.004.
Katsutoshi Hara 1 Naoki Takahashi 2 Akira Wakamatsu 3 Stephen Caltabiano 4
Affiliations

Affiliations

  • 1 Clinical Pharmacology, GlaxoSmithKline K.K., 6-15, Sendagaya 4-chome, Shibuya-ku, Tokyo 151-8566, Japan. Electronic address: katsutoshi.2.hara@gsk.com.
  • 2 Clinical Pharmacology, GlaxoSmithKline K.K., 6-15, Sendagaya 4-chome, Shibuya-ku, Tokyo 151-8566, Japan.
  • 3 Pre-Clinical Development, GlaxoSmithKline K.K., 6-15, Sendagaya 4-chome, Shibuya-ku, Tokyo 151-8566, Japan.
  • 4 Clinical Pharmacology, GlaxoSmithKline plc, 2301 Renaissance Boulevard, King of Prussia 19406, PA, United States.
Abstract

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.

Keywords

Anemia; Erythropoietin; GSK1278863; Hypoxia-inducible factor; PK–PD; Pharmacodynamics; Pharmacokinetics; Prolyl hydroxylase inhibitor; Reticulocytes.

Figures
Products