Roxadustat
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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Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Treatment of Anemia •••••••••••• ••••• - 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
Target Actions Organism AEgl nine homolog 1 inhibitorHumans AEgl nine homolog 2 inhibitorHumans AEgl nine homolog 3 inhibitorHumans - 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 Browse all" title="About SNP Mediated Effects/ADRs" id="snp-actions-info" class="drug-info-popup" href="javascript:void(0);">
- Not Available
Interactions
- Drug Interactions Learn More" title="About Drug Interactions" id="structured-interactions-info" class="drug-info-popup" href="javascript:void(0);">
- 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.
Drug Interaction Integrate drug-drug
interactions in your softwareAbatacept The metabolism of Roxadustat can be increased when combined with Abatacept. Abemaciclib The serum concentration of Abemaciclib can be increased when it is combined with Roxadustat. Abiraterone The metabolism of Roxadustat can be decreased when combined with Abiraterone. Adalimumab The metabolism of Roxadustat can be increased when combined with Adalimumab. Afatinib The serum concentration of Afatinib can be increased when it is combined with Roxadustat. - Food Interactions
- Take with or without food. Food can decrease Cmax but not to a clinically significant extent.
Products
- Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.
- Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Evrenzo Tablet, film coated 70 mg Oral Astellas Pharma Europe Bv 2023-06-20 Not applicable EU Evrenzo Tablet, film coated 150 mg Oral Astellas Pharma Europe Bv 2021-10-06 Not applicable EU Evrenzo Tablet, film coated 50 mg Oral Astellas Pharma Europe Bv 2021-10-06 Not applicable EU Evrenzo Tablet, film coated 150 mg Oral Astellas Pharma Europe Bv 2023-06-20 Not applicable EU Evrenzo Tablet, film coated 50 mg Oral Astellas Pharma Europe Bv 2023-06-20 Not applicable EU
Categories
- ATC Codes
- B03XA05 — Roxadustat
- Drug Categories
- Amino Acids
- Amino Acids, Peptides, and Proteins
- Antianemic Preparations
- BCRP/ABCG2 Inhibitors
- Blood and Blood Forming Organs
- Cytochrome P-450 CYP2C8 Substrates
- Cytochrome P-450 Substrates
- Heterocyclic Compounds, Fused-Ring
- Hypoxia-Inducible Factor-Proline Dioxygenases, antagonists & inhibitors
- OAT1/SLC22A6 Substrates
- OAT3/SLC22A8 Substrates
- OATP1B1/SLCO1B1 Inhibitors
- UGT1A9 Substrates
- 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
- Dhillon S: Roxadustat: First Global Approval. Drugs. 2019 Apr;79(5):563-572. doi: 10.1007/s40265-019-01077-1. [Article]
- 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]
- 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]
- 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]
- EMA Approved Drug Products: Evrenzo (roxadustat) oral tablets [Link]
- European Medicines Agency: Evrenzo (roxadustat) [Link]
- External Links
- 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 Learn More" title="About Clinical Trials" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">
Phase Status Purpose Conditions Count 4 Completed Treatment Anemia of Chronic Kidney Disease / Coronavirus Disease 2019 (COVID‑19) 1 4 Completed Treatment CKD Anemia in Dialysis Participants 1 4 Completed Treatment Renal Anemia 1 4 Not Yet Recruiting Treatment Anemia / Chronic Kidney Disease (CKD) / Heart Failure 1 4 Not Yet Recruiting Treatment Myelodysplastic Syndrome 1
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Tablet Oral 20.000 mg Tablet, film coated Oral 100 MG Tablet, film coated Oral 150 MG Tablet, film coated Oral 20 MG Tablet, film coated Oral 50 MG Tablet, film coated Oral 70 MG - Prices
- Not Available
- Patents
- Not Available
Properties
- State
- Solid
- Experimental Properties
Property Value Source water solubility <1 mg/mL https://www.selleck.cn/msds/MSDS_S1007.pdf - Predicted Properties
Property Value Source Water Solubility 0.0115 mg/mL ALOGPS logP 3.13 ALOGPS logP 1.85 Chemaxon logS -4.5 ALOGPS pKa (Strongest Acidic) 2.75 Chemaxon pKa (Strongest Basic) 3.84 Chemaxon Physiological Charge -1 Chemaxon Hydrogen Acceptor Count 5 Chemaxon Hydrogen Donor Count 3 Chemaxon Polar Surface Area 108.75 Å2 Chemaxon Rotatable Bond Count 5 Chemaxon Refractivity 92.85 m3·mol-1 Chemaxon Polarizability 35.7 Å3 Chemaxon Number of Rings 3 Chemaxon Bioavailability 1 Chemaxon Rule of Five Yes Chemaxon Ghose Filter Yes Chemaxon Veber's Rule No Chemaxon MDDR-like Rule No Chemaxon - Predicted ADMET Features
- Not Available
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
Spectrum Spectrum Type Splash Key Predicted MS/MS Spectrum - 10V, Positive (Annotated) Predicted LC-MS/MS splash10-0fb9-0094000000-5fa2a554790260a200e3 Predicted MS/MS Spectrum - 10V, Negative (Annotated) Predicted LC-MS/MS splash10-0udi-2191000000-6a98524a2152111d3213 Predicted MS/MS Spectrum - 20V, Negative (Annotated) Predicted LC-MS/MS splash10-0uk9-1490000000-c20b0c84b5085991f0ff Predicted MS/MS Spectrum - 20V, Positive (Annotated) Predicted LC-MS/MS splash10-0fb9-1092000000-466e1a76a8b5923b6bca Predicted MS/MS Spectrum - 40V, Negative (Annotated) Predicted LC-MS/MS splash10-006t-7792000000-1d7d20f03c0c4ce0be7b Predicted MS/MS Spectrum - 40V, Positive (Annotated) Predicted LC-MS/MS splash10-004i-7092000000-41e9ffec24b1c12d2224 Predicted 1H NMR Spectrum 1D NMR Not Applicable Predicted 13C NMR Spectrum 1D NMR Not Applicable - Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 207.4923845 predictedDarkChem Lite v0.1.0 [M-H]- 179.9332 predictedDeepCCS 1.0 (2019) [M+H]+ 207.1968845 predictedDarkChem Lite v0.1.0 [M+H]+ 182.29118 predictedDeepCCS 1.0 (2019) [M+Na]+ 207.6008845 predictedDarkChem Lite v0.1.0 [M+Na]+ 189.44646 predictedDeepCCS 1.0 (2019)
Targets
![](https://go.drugbank.com/assets/locked/DrugTargets2-682eb846d210ae4bf33ca03febccfb57bb1c61318e699b729e5df4dfab2c5b67.png)
- 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
- 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
- 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
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
- 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
- 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
- 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
- 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
- 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
- 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
- EMA Approved Drug Products: Evrenzo (roxadustat) oral tablets [Link]
Drug created at October 18, 2007 19:34 / Updated at February 18, 2022 00:37