Iron Regulation by Molidustat, a Daily Oral Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitor, in Patients with Chronic Kidney Disease.
Administration, Oral
Aged
Aged, 80 and over
Anemia
/ blood
Basic Helix-Loop-Helix Transcription Factors
/ metabolism
Double-Blind Method
Female
Hematinics
/ administration & dosage
Hemoglobins
/ metabolism
Hepcidins
/ blood
Humans
Hypoxia-Inducible Factor 1, alpha Subunit
/ metabolism
Iron
/ blood
Male
Middle Aged
Prolyl-Hydroxylase Inhibitors
/ administration & dosage
Pyrazoles
/ administration & dosage
Renal Insufficiency, Chronic
/ blood
Triazoles
/ administration & dosage
Anemia
Chronic kidney disease
Hypoxia-inducible factor prolyl hydroxylase inhibitor
Iron metabolism
Molidustat
Journal
Nephron
ISSN: 2235-3186
Titre abrégé: Nephron
Pays: Switzerland
ID NLM: 0331777
Informations de publication
Date de publication:
2019
2019
Historique:
received:
25
02
2019
accepted:
09
07
2019
pubmed:
7
8
2019
medline:
11
7
2020
entrez:
7
8
2019
Statut:
ppublish
Résumé
The current treatment for anemia associated with chronic kidney disease (CKD) includes the administration of erythropoiesis stimulating agents (ESAs) combined with iron supplementation. Molidustat, a hypoxia-inducible factor prolyl hydroxylase inhibitor, has potential to treat anemia associated with CKD through increased erythropoietin production and improved iron availability. Here, we report the effect of molidustat on iron metabolism. Parameters of iron metabolism were monitored in three 16-week, randomized, controlled, phase 2 studies assessing the safety and efficacy of molidustat in the treatment of anemia associated with CKD in different populations: treatment-naïve and previously ESA-treated patients not on dialysis, and previously ESA-treated patients on hemodialysis. Iron supplementation was left at the discretion of the investigator. In treatment-naïve patients not on dialysis, transferrin saturation (TSAT), hepcidin, ferritin, and iron concentrations decreased with molidustat, whereas total iron binding capacity (TIBC) increased. Similar results were observed in previously ESA-treated patients not on dialysis, although changes in those parameters were larger in treatment-naïve than in previously ESA-treated patients. In previously ESA-treated patients receiving hemodialysis, hepcidin concentration and TIBC remained stable with molidustat, whereas TSAT and ferritin and iron concentrations increased. Generally, similar trends were observed in secondary analyses of subgroups of patients not receiving iron supplementation. Molidustat is a potential alternative to standard treatment of anemia associated with CKD, with a different mechanism of action. In patients not receiving dialysis, molidustat increases iron availability. In patients receiving hemodialysis, further investigation is required to understand fully the mechanisms underlying iron mobilization associated with molidustat.
Sections du résumé
BACKGROUND/AIMS
The current treatment for anemia associated with chronic kidney disease (CKD) includes the administration of erythropoiesis stimulating agents (ESAs) combined with iron supplementation. Molidustat, a hypoxia-inducible factor prolyl hydroxylase inhibitor, has potential to treat anemia associated with CKD through increased erythropoietin production and improved iron availability. Here, we report the effect of molidustat on iron metabolism.
METHOD
Parameters of iron metabolism were monitored in three 16-week, randomized, controlled, phase 2 studies assessing the safety and efficacy of molidustat in the treatment of anemia associated with CKD in different populations: treatment-naïve and previously ESA-treated patients not on dialysis, and previously ESA-treated patients on hemodialysis. Iron supplementation was left at the discretion of the investigator.
RESULTS
In treatment-naïve patients not on dialysis, transferrin saturation (TSAT), hepcidin, ferritin, and iron concentrations decreased with molidustat, whereas total iron binding capacity (TIBC) increased. Similar results were observed in previously ESA-treated patients not on dialysis, although changes in those parameters were larger in treatment-naïve than in previously ESA-treated patients. In previously ESA-treated patients receiving hemodialysis, hepcidin concentration and TIBC remained stable with molidustat, whereas TSAT and ferritin and iron concentrations increased. Generally, similar trends were observed in secondary analyses of subgroups of patients not receiving iron supplementation.
CONCLUSIONS
Molidustat is a potential alternative to standard treatment of anemia associated with CKD, with a different mechanism of action. In patients not receiving dialysis, molidustat increases iron availability. In patients receiving hemodialysis, further investigation is required to understand fully the mechanisms underlying iron mobilization associated with molidustat.
Identifiants
pubmed: 31387097
pii: 000502012
doi: 10.1159/000502012
pmc: PMC6979436
doi:
Substances chimiques
Basic Helix-Loop-Helix Transcription Factors
0
HIF1A protein, human
0
Hematinics
0
Hemoglobins
0
Hepcidins
0
Hypoxia-Inducible Factor 1, alpha Subunit
0
Prolyl-Hydroxylase Inhibitors
0
Pyrazoles
0
Triazoles
0
endothelial PAS domain-containing protein 1
1B37H0967P
molidustat
9JH486CZ13
Iron
E1UOL152H7
Types de publication
Clinical Trial, Phase II
Journal Article
Randomized Controlled Trial
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
243-254Informations de copyright
© 2019 The Author(s). Published by S. Karger AG, Basel.
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