title: Effects of Daprodustat, a Novel Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitor on Anemia Management in Japanese Hemodialysis Subjects.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Graduate School of Health Care Sciences, Jikei Institute, Osaka, Japan.
authors.forename: Tadao
authors.initials: T
authors.lastname: Akizawa
authors.forename: Yoshiharu
authors.initials: Y
authors.lastname: Tsubakihara
authors.forename: Masaomi
authors.initials: M
authors.lastname: Nangaku
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Endo
authors.forename: Hiromu
authors.initials: H
authors.lastname: Nakajima
authors.forename: Tomoko
authors.initials: T
authors.lastname: Kohno
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Imai
authors.forename: Natsumi
authors.initials: N
authors.lastname: Kawase
authors.forename: Katsutoshi
authors.initials: K
authors.lastname: Hara
authors.forename: John
authors.initials: J
authors.lastname: Lepore
authors.forename: Alexander
authors.initials: A
authors.lastname: Cobitz
mesh_terms: D000368:Aged; D000740:Anemia / Q000188:drug therapy* / Q000209:etiology; D001463:Barbiturates / Q000494:pharmacology / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004921:Erythropoietin / Q000097:blood; D005260:Female; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D006454:Hemoglobins / Q000032:analysis; D006801:Humans; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases / Q000037:antagonists & inhibitors*; D007564:Japan; D008297:Male; D008875:Middle Aged; D064800:Prolyl-Hydroxylase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D006435:Renal Dialysis; D051436:Renal Insufficiency, Chronic / Q000097:blood / Q000150:complications / Q000628:therapy*; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000097:blood
chemical_list: D001463:Barbiturates; C554270:EPO protein, human; C000599718:GSK1278863; D006454:Hemoglobins; D064800:Prolyl-Hydroxylase Inhibitors; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D004921:Erythropoietin; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D005998:Glycine