Effects of Daprodustat, a Novel Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitor on Anemia Management in Japanese Hemodialysis Subjects

• Published in: American journal of nephrology Vol. 45; no. 2; p. 127
• Main Authors: Akizawa, Tadao, Tsubakihara, Yoshiharu, Nangaku, Masaomi, Endo, Yukihiro, Nakajima, Hiromu, Kohno, Tomoko, Imai, Yukiko, Kawase, Natsumi, Hara, Katsutoshi, Lepore, John, Cobitz, Alexander
• Format: Journal Article
• Language: English
• Published: Switzerland 01-01-2017
• Subjects: Aged; Anemia - drug therapy; Anemia - etiology; Barbiturates - pharmacology; Barbiturates - therapeutic use; Dose-Response Relationship, Drug; Double-Blind Method; Erythropoietin - blood; Female; Glycine - analogs & derivatives; Glycine - pharmacology; Glycine - therapeutic use; Hemoglobins - analysis; Humans; Hypoxia-Inducible Factor-Proline Dioxygenases - antagonists & inhibitors; Japan; Male; Middle Aged; Prolyl-Hydroxylase Inhibitors - pharmacology; Prolyl-Hydroxylase Inhibitors - therapeutic use; Renal Dialysis; Renal Insufficiency, Chronic - blood; Renal Insufficiency, Chronic - complications; Renal Insufficiency, Chronic - therapy; Treatment Outcome; Vascular Endothelial Growth Factor A - blood
• ISSN: 1421-9670
• DOI: 10.1159/000454818

Daprodustat (GSK1278863) is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor being developed for treatment of anemia associated with chronic kidney disease (CKD). The effect of daprodustat in Japanese CKD patients with anemia has not been previously investigated.
We evaluated the relationship between daprodustat dose and hemoglobin response in Japanese patients on hemodialysis (HD) with anemia in a 4-week, phase II, double-blind, placebo-controlled study. After interrupting their erythropoiesis-stimulating agent for between 2 and 8 weeks, subjects with hemoglobin 8.5-10.5 g/dL were randomized to placebo or daprodustat 4, 6, 8, or 10 mg orally once daily. Hemoglobin, erythropoietin (EPO), and vascular endothelial growth factor (VEGF) levels during therapy were evaluated.
Eighty-six of 97 randomized subjects completed the study. Mean baseline hemoglobin ranged from 9.68 to 9.92 g/dL across groups. After 4-week administration, mean hemoglobin changes were -0.28, -0.01, 0.54, and 0.97 g/dL in the 4, 6, 8, and 10 mg groups, respectively, as compared to -1.41 g/dL for placebo. Dose-dependent increase in plasma EPO concentration were observed up to 8 mg, with the 10 mg dose responses being similar to 8 mg. Plasma VEGF concentrations were minimally changed, even though 5 subjects treated with 6-10 mg reached EPO >500 mIU/mL.
Daprodustat 4-10 mg once-daily produced dose-dependent increase in hemoglobin relative to placebo in Japanese HD subjects. The doses evaluated in the study have moderately increased endogenous EPO without changes in circulating VEGF levels.