Identification

Summary

Roxadustat is a hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor used to treat symptomatic anemia associated with chronic kidney disease.

Generic Name
Roxadustat
DrugBank Accession Number
DB04847
Background

Roxadustat is a first-in-class hypoxia-inducible factor prolyl hydroxylase inhibitor used to treat anemia associated with chronic kidney disease. It works by reducing the breakdown of the hypoxia-inducible factor (HIF), which is a transcription factor that stimulates red blood cell production in response to low oxygen levels.2 Roxadustat was first approved by the European Commission in August 2021.6

Type
Small Molecule
Groups
Approved, Investigational
Structure
Weight
Average: 352.346
Monoisotopic: 352.105921623
Chemical Formula
C19H16N2O5
Synonyms
  • Roxadustat
  • Roxadustatum
External IDs
  • ASP 1517
  • ASP-1517
  • ASP1517
  • FG 4592
  • FG-4592
  • FG4592

Pharmacology

Indication

Roxadustat is indicated for the treatment of adult patients with symptomatic anemia associated with chronic kidney disease (CKD).5

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Associated Conditions
Contraindications & Blackbox Warnings
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Pharmacodynamics

Roxadustat dose-dependently improves iron bioavailability, increases hemoglobin production, and increases red blood cell mass in patients with anemia.5 In non-dialysis-dependent CKD patients with anemia, roxadustat maintained Hb for up to 2 years. It has a comparable efficacy to erythropoietin-stimulating agents in achieving Hb response.2 Roxadustat also reduces cholesterol levels from baseline, regardless of the use of statins or other lipid-lowering agents.1

Mechanism of action

Anemia is a common complication of chronic kidney disease that may be caused by reduced production of renal erythropoietin (EPO), functional iron deficiency due to increased levels of hepcidin, blood loss, reduced erythrocyte survival duration, and inflammation.1,2 Hypoxia-inducible factor (HIF) is a transcription factor that induces several target oxygen-sensitive genes in response to low oxygen levels in the cellular environment, or hypoxia. Target genes are involved in erythropoiesis, such as those for EPO, EPO receptor, proteins promoting iron absorption, iron transport, and haem synthesis.1 Activation of the HIF pathway is an important adaptive responsive to hypoxia to increase red blood cell production.5 HIF is heterodimeric and contains an oxygen-regulated α-subunit. The α-subunit houses an oxygen-dependent degradation (ODD) domain that is regulated and hydroxylated by HIF-prolyl hydroxylase (HIF-PHD) enzymes under normoxic cellular conditions.3 HIF-PHD enzymes play a crucial role in maintaining a balance between oxygen availability and HIF activity.1

Roxadustat is a reversible and potent inhibitor of HIF-PHD enzymes: inhibition of HIF-PHD leads to the accumulation of functional HIF, an increase in plasma endogenous EPO production, enhanced erythropoiesis, and indirect suppression of hepcidin, which is an iron regulator protein that is increased during inflammation in chronic kidney disease.5 Roxadustat can also regulate iron transporter proteins 5 and regulates iron metabolism by increasing serum transferrin, intestinal iron absorption and the release of stored iron in patients with anemia associated with dialysis-dependent or dialysis-independent CKD.1 Overall, roxadustat improves iron bioavailability, increases Hb production, and increases red cell mass.1,5

TargetActionsOrganism
AEgl nine homolog 1
inhibitor
Humans
AEgl nine homolog 2
inhibitor
Humans
AEgl nine homolog 3
inhibitor
Humans
Absorption

Roxadustat plasma exposure (AUC and Cmax) increases dose-proportionally within the recommended therapeutic dose range. In a three times per week dosing regimen, steady-state roxadustat plasma concentrations are achieved within one week (three doses) with minimal accumulation. Maximum plasma concentrations (Cmax) are usually achieved at two hours post dose in the fasted state. Administration of roxadustat with food decreased Cmax by 25% but did not alter AUC as compared with the fasted state.5

Volume of distribution

The blood-to-plasma ratio of roxadustat is 0.6. The apparent volume of distribution at steady-state is 24 L.5

Protein binding

Roxadustat is highly bound to human plasma proteins (approximately 99%), mainly to albumin.5

Metabolism

In vitro, roxadustat is a substrate for CYP2C8 and UGT1A9 enzymes. Roxadustat is primarily metabolized to hydroxy-roxadustat and roxadustat O-glucuronide. Unchanged roxadustat was the major circulating component in human plasma and detectable metabolites in human plasma constituted less than 10% of total drug-related material exposure. No human-specific metabolites were observed 5 but roxadustat O-glucuronide was detected in human urine sample.4

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Route of elimination

Following oral administration of radiolabelled roxadustat in healthy subjects, the mean recovery of radioactivity was 96% (50% in feces, 46% in urine). In feces, 28% of the dose was excreted as unchanged roxadustat. Less than 2% of the dose was recovered in urine as unchanged roxadustat.5

Half-life

The mean effective half-life of roxadustat is approximately 15 hours in patients with CKD.5

Clearance

The apparent total body clearance (CL/F) of roxadustat is 1.1 L/h in patients with CKD not on dialysis and 1.4 L/h in patients with CKD on dialysis.5

Adverse Effects
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Toxicity

There are limited information on the LD50 values of roxadustat.

Single doses of roxadustat 5 mg/kg (up to 510 mg) in healthy subjects led to a transient increase in heart rate, an increased frequency of mild to moderate musculoskeletal pain, headaches, sinus tachycardia, and less commonly, low blood pressure. All these effects were non-serious in nature. Roxadustat overdose can elevate hemoglobin levels above the desired level (10 - 12 g/dL), which should be managed with discontinuation of roxadustat treatment or reduction of drug dosage with careful monitoring and appropriate supportive treatment. Roxadustat and its metabolites are not significantly removed by hemodialysis.5

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AbataceptThe metabolism of Roxadustat can be increased when combined with Abatacept.
AbemaciclibThe serum concentration of Abemaciclib can be increased when it is combined with Roxadustat.
AbirateroneThe metabolism of Roxadustat can be decreased when combined with Abiraterone.
AdalimumabThe metabolism of Roxadustat can be increased when combined with Adalimumab.
AfatinibThe serum concentration of Afatinib can be increased when it is combined with Roxadustat.
AllopurinolThe serum concentration of Allopurinol can be increased when it is combined with Roxadustat.
AlmotriptanThe metabolism of Roxadustat can be decreased when combined with Almotriptan.
AlpelisibThe serum concentration of Alpelisib can be increased when it is combined with Roxadustat.
AluminiumAluminium can cause a decrease in the absorption of Roxadustat resulting in a reduced serum concentration and potentially a decrease in efficacy.
Aluminium phosphateAluminium phosphate can cause a decrease in the absorption of Roxadustat resulting in a reduced serum concentration and potentially a decrease in efficacy.
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Food Interactions
  • Take with or without food. Food can decrease Cmax but not to a clinically significant extent.

Products

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Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
EvrenzoTablet, film coated100 mgOralAstellas Pharma Europe Bv2021-10-06Not applicableEU flag
EvrenzoTablet, film coated20 mgOralAstellas Pharma Europe Bv2021-10-06Not applicableEU flag
EvrenzoTablet, film coated70 mgOralAstellas Pharma Europe Bv2021-10-06Not applicableEU flag
EvrenzoTablet, film coated150 mgOralAstellas Pharma Europe Bv2021-10-06Not applicableEU flag
EvrenzoTablet, film coated50 mgOralAstellas Pharma Europe Bv2021-10-06Not applicableEU flag

Categories

ATC Codes
B03XA05 — Roxadustat
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as n-acyl-alpha amino acids. These are compounds containing an alpha amino acid which bears an acyl group at its terminal nitrogen atom.
Kingdom
Organic compounds
Super Class
Organic acids and derivatives
Class
Carboxylic acids and derivatives
Sub Class
Amino acids, peptides, and analogues
Direct Parent
N-acyl-alpha amino acids
Alternative Parents
Diarylethers / Isoquinolines and derivatives / Pyridinecarboxylic acids and derivatives / 2-heteroaryl carboxamides / Phenol ethers / Phenoxy compounds / Methylpyridines / Hydroxypyridines / Heteroaromatic compounds / Vinylogous acids
show 8 more
Substituents
2-heteroaryl carboxamide / Aromatic heteropolycyclic compound / Azacycle / Benzenoid / Carbonyl group / Carboxamide group / Carboxylic acid / Diaryl ether / Ether / Heteroaromatic compound
show 19 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
X3O30D9YMX
CAS number
808118-40-3
InChI Key
YOZBGTLTNGAVFU-UHFFFAOYSA-N
InChI
InChI=1S/C19H16N2O5/c1-11-15-9-13(26-12-5-3-2-4-6-12)7-8-14(15)18(24)17(21-11)19(25)20-10-16(22)23/h2-9,24H,10H2,1H3,(H,20,25)(H,22,23)
IUPAC Name
2-[(4-hydroxy-1-methyl-7-phenoxyisoquinolin-3-yl)formamido]acetic acid
SMILES
CC1=NC(C(=O)NCC(O)=O)=C(O)C2=C1C=C(OC1=CC=CC=C1)C=C2

References

General References
  1. Dhillon S: Roxadustat: First Global Approval. Drugs. 2019 Apr;79(5):563-572. doi: 10.1007/s40265-019-01077-1. [Article]
  2. Barratt J, Andric B, Tataradze A, Schomig M, Reusch M, Valluri U, Mariat C: Roxadustat for the treatment of anaemia in chronic kidney disease patients not on dialysis: a Phase 3, randomized, open-label, active-controlled study (DOLOMITES). Nephrol Dial Transplant. 2021 Aug 27;36(9):1616-1628. doi: 10.1093/ndt/gfab191. [Article]
  3. Ziello JE, Jovin IS, Huang Y: Hypoxia-Inducible Factor (HIF)-1 regulatory pathway and its potential for therapeutic intervention in malignancy and ischemia. Yale J Biol Med. 2007 Jun;80(2):51-60. [Article]
  4. Hansson A, Thevis M, Cox H, Miller G, Eichner D, Bondesson U, Hedeland M: Investigation of the metabolites of the HIF stabilizer FG-4592 (roxadustat) in five different in vitro models and in a human doping control sample using high resolution mass spectrometry. J Pharm Biomed Anal. 2017 Feb 5;134:228-236. doi: 10.1016/j.jpba.2016.11.041. Epub 2016 Nov 27. [Article]
  5. EMA Approved Drug Products: Evrenzo (roxadustat) oral tablets [Link]
  6. European Medicines Agency: Evrenzo (roxadustat) [Link]
KEGG Drug
D10593
PubChem Compound
11256664
PubChem Substance
347827699
ChemSpider
9431690
BindingDB
50431015
ChEBI
132774
ChEMBL
CHEMBL2338329
ZINC
ZINC000071257465
PDBe Ligand
8HO
Wikipedia
Roxadustat
PDB Entries
6kkb / 6kke / 6knu / 6knv / 6knw

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4CompletedTreatmentAnemia of Chronic Kidney Disease / Coronavirus Disease 2019 (COVID‑19)1
4CompletedTreatmentCKD Anemia in Dialysis Participants1
4CompletedTreatmentRenal Anemia1
3CompletedTreatmentAnemia4
3CompletedTreatmentAnemia Associated With End Stage Renal Disease (ESRD)2
3CompletedTreatmentAnemia in Chronic Kidney Disease in Non-dialysis Patients2
3CompletedTreatmentAnemia in Incident Dialysis Patients1
3CompletedTreatmentAnemia / End Stage Renal Disease (ESRD)1
3CompletedTreatmentChronic Kidney Disease (CKD)2
3CompletedTreatmentCKD Anemia1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Tablet, film coatedOral100 MG
Tablet, film coatedOral150 MG
Tablet, film coatedOral20 MG
Tablet, film coatedOral50 MG
Tablet, film coatedOral70 MG
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
water solubility<1 mg/mLhttps://www.selleck.cn/msds/MSDS_S1007.pdf
Predicted Properties
PropertyValueSource
Water Solubility0.0115 mg/mLALOGPS
logP3.13ALOGPS
logP1.85ChemAxon
logS-4.5ALOGPS
pKa (Strongest Acidic)2.75ChemAxon
pKa (Strongest Basic)3.84ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count3ChemAxon
Polar Surface Area108.75 Å2ChemAxon
Rotatable Bond Count5ChemAxon
Refractivity92.85 m3·mol-1ChemAxon
Polarizability35.7 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Targets

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insights and accelerate drug research.
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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Peptidyl-proline dioxygenase activity
Specific Function
Cellular oxygen sensor that catalyzes, under normoxic conditions, the post-translational formation of 4-hydroxyproline in hypoxia-inducible factor (HIF) alpha proteins. Hydroxylates a specific prol...
Gene Name
EGLN1
Uniprot ID
Q9GZT9
Uniprot Name
Egl nine homolog 1
Molecular Weight
46020.585 Da
References
  1. Dhillon S: Roxadustat: First Global Approval. Drugs. 2019 Apr;79(5):563-572. doi: 10.1007/s40265-019-01077-1. [Article]
  2. EMA Approved Drug Products: Evrenzo (roxadustat) oral tablets [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Peptidyl-proline 4-dioxygenase activity
Specific Function
Cellular oxygen sensor that catalyzes, under normoxic conditions, the post-translational formation of 4-hydroxyproline in hypoxia-inducible factor (HIF) alpha proteins. Hydroxylates a specific prol...
Gene Name
EGLN2
Uniprot ID
Q96KS0
Uniprot Name
Egl nine homolog 2
Molecular Weight
43650.03 Da
References
  1. Dhillon S: Roxadustat: First Global Approval. Drugs. 2019 Apr;79(5):563-572. doi: 10.1007/s40265-019-01077-1. [Article]
  2. EMA Approved Drug Products: Evrenzo (roxadustat) oral tablets [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Peptidyl-proline 4-dioxygenase activity
Specific Function
Cellular oxygen sensor that catalyzes, under normoxic conditions, the post-translational formation of 4-hydroxyproline in hypoxia-inducible factor (HIF) alpha proteins. Hydroxylates a specific prol...
Gene Name
EGLN3
Uniprot ID
Q9H6Z9
Uniprot Name
Egl nine homolog 3
Molecular Weight
27261.06 Da
References
  1. Dhillon S: Roxadustat: First Global Approval. Drugs. 2019 Apr;79(5):563-572. doi: 10.1007/s40265-019-01077-1. [Article]
  2. EMA Approved Drug Products: Evrenzo (roxadustat) oral tablets [Link]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Steroid hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP2C8
Uniprot ID
P10632
Uniprot Name
Cytochrome P450 2C8
Molecular Weight
55824.275 Da
References
  1. EMA Approved Drug Products: Evrenzo (roxadustat) oral tablets [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Retinoic acid binding
Specific Function
UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. This isoform has specificity for phenols. Isoform 2 lacks trans...
Gene Name
UGT1A9
Uniprot ID
O60656
Uniprot Name
UDP-glucuronosyltransferase 1-9
Molecular Weight
59940.495 Da
References
  1. EMA Approved Drug Products: Evrenzo (roxadustat) oral tablets [Link]

Carriers

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Binder
General Function
Toxic substance binding
Specific Function
Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloid...
Gene Name
ALB
Uniprot ID
P02768
Uniprot Name
Serum albumin
Molecular Weight
69365.94 Da
References
  1. EMA Approved Drug Products: Evrenzo (roxadustat) oral tablets [Link]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Xenobiotic-transporting atpase activity
Specific Function
High-capacity urate exporter functioning in both renal and extrarenal urate excretion. Plays a role in porphyrin homeostasis as it is able to mediates the export of protoporhyrin IX (PPIX) both fro...
Gene Name
ABCG2
Uniprot ID
Q9UNQ0
Uniprot Name
ATP-binding cassette sub-family G member 2
Molecular Weight
72313.47 Da
References
  1. EMA Approved Drug Products: Evrenzo (roxadustat) oral tablets [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Mediates the Na(+)-independent uptake of organic anions such as pravastatin, taurocholate, methotrexate, dehydroepiandrosterone sulfate, 17-beta-glucuronosyl estradiol, estrone sulfate, prostagland...
Gene Name
SLCO1B1
Uniprot ID
Q9Y6L6
Uniprot Name
Solute carrier organic anion transporter family member 1B1
Molecular Weight
76447.99 Da
References
  1. EMA Approved Drug Products: Evrenzo (roxadustat) oral tablets [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Involved in the renal elimination of endogenous and exogenous organic anions. Functions as organic anion exchanger when the uptake of one molecule of organic anion is coupled with an efflux of one ...
Gene Name
SLC22A6
Uniprot ID
Q4U2R8
Uniprot Name
Solute carrier family 22 member 6
Molecular Weight
61815.78 Da
References
  1. EMA Approved Drug Products: Evrenzo (roxadustat) oral tablets [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Plays an important role in the excretion/detoxification of endogenous and exogenous organic anions, especially from the brain and kidney. Involved in the transport basolateral of steviol, fexofenad...
Gene Name
SLC22A8
Uniprot ID
Q8TCC7
Uniprot Name
Solute carrier family 22 member 8
Molecular Weight
59855.585 Da
References
  1. EMA Approved Drug Products: Evrenzo (roxadustat) oral tablets [Link]

Drug created at October 18, 2007 19:34 / Updated at February 18, 2022 00:37