Identification
- Summary
Cedazuridine is a cytidine deaminase inhibitor coadministered with the hypomethylating agent decitabine for the treatment of variable forms of myelodysplastic syndrome (MDS).
- Brand Names
- Inqovi 5 Tablet Pack
- Generic Name
- Cedazuridine
- DrugBank Accession Number
- DB15694
- Background
Myelodysplastic syndromes (MDS) are a group of hematopoietic neoplasms that give rise to variable cytopenias progressing to secondary acute myeloid leukemia (sAML), which is invariably fatal if untreated.1,2,3 Hypomethylating agents such as decitabine and azacitidine are used to treat MDS through inducing DNA hypomethylation and apoptosis of cancerous cells.7,8 Although effective, these compounds are rapidly metabolized by cytidine deaminase (CDA) prior to reaching systemic circulation when administered orally, necessitating intramuscular or intravenous administration routes.4,5,6,7 Cedazuridine is a fluorinated tetrahydrouridine derivative specifically designed to inhibit CDA and facilitate oral administration of hypomethylating agents.4,5,6,7,8
Cedazuridine was first reported in 2014,4 and was subsequently approved by the FDA on July 7, 2020, in combination with decitabine for sale by Astex Pharmaceuticals Inc under the name INQOVI®.8
- Type
- Small Molecule
- Groups
- Approved, Investigational
- Structure
Structure for Cedazuridine (DB15694)
- Weight
- Average: 268.217
Monoisotopic: 268.087077885 - Chemical Formula
- C9H14F2N2O5
- Synonyms
- (4R)-2'-Deoxy-2',2'-difluoro-3,4,5,6-tetrahydrouridine
- Cedazuridine
- External IDs
- ASTX-727 component cedazuridine
- ASTX727 component cedazuridine
- E-7727
- E7727
- WHO 10741
Pharmacology
- Indication
Cedazuridine, in combination with decitabine, is indicated for the treatment of myelodysplastic syndromes (MDS), including MDS with refractory anemia, MDS with refractory anemia and ringed sideroblasts, MDS with refractory anemia and excess blasts, MDS scoring intermediate-1, intermediate-2, or high-risk on the International Prognostic Scoring System (IPSS), and chronic myelomonocytic leukemia (CMML).8
Reduce drug development failure ratesBuild, train, & validate machine-learning modelswith evidence-based and structured datasets.Build, train, & validate predictive machine-learning models with structured datasets.- Associated Conditions
- Contraindications & Blackbox Warnings
Avoid life-threatening adverse drug eventsImprove clinical decision support with information on contraindications & blackbox warnings, population restrictions, harmful risks, & more.Avoid life-threatening adverse drug events & improve clinical decision support.- Pharmacodynamics
Cedazuridine is a cytidine deaminase inhibitor that is co-administered with hypomethylating agents such as decitabine in order to increase their oral bioavailability.4,5,6,7 In combination with hypomethylating agents, cedazuridine may cause myelosuppression and embryo-fetal toxicity and should be administered with appropriate monitoring.8
- Mechanism of action
Myelodysplastic syndromes (MDS) represent a heterogeneous group of hematopoietic neoplasms arising from a variety of underlying mutations that manifest in peripheral cytopenias and may eventually progress to secondary acute myeloid leukemia (sAML). There are over 45 genes commonly mutated in MDS patients, including those involved in DNA methylation and repair, histone modification, RNA splicing, transcription, signal transduction, and cellular adhesion. It is hypothesized that initial clonal founder mutations give rise to progressive acquisition of secondary mutations and facilitate disease progression to sAML.1,2,3
Hypomethylating agents such as decitabine are metabolized into triphosphate derivatives that are subsequently incorporated into DNA. Once incorporated, these agents inhibit the activity of DNA methylases such as DNMT1, leading to progressive DNA hypomethylation and eventual activation of tumour suppression genes and apoptotic pathways.7,8 However, hypomethylating agents given orally are vulnerable to first-pass metabolism by cytidine deaminase, and hence typically have to be administered through intramuscular or intravenous routes.4,5,6,7 Co-administration with cedazuridine, which is an efficient inhibitor of cytidine deaminase,4,8 drastically increases the oral bioavailability of decitabine, allowing for combination oral therapy.4,5,6,7,8
Target Actions Organism ACytidine deaminase inhibitorHumans - Absorption
Cedazuridine (100 mg) taken orally with decitabine (35 mg) once daily for five days resulted in a day 1 AUC and steady-state AUC (coefficient of variation) of 103 (55%) and 178 (53%) ng*hr/mL for decitabine and 2950 (49%) and 3291 (45%) ng*hr/mL for cedazuridine, respectively. Overall, the 5-day cumulative AUC for decitabine was 851 (50%). Similarly, the Cmax for decitabine and cedazuridine was 145 (55%) and 371 (52%) ng/mL, respectively. The median Tmax for decitabine was 1 hr (range 0.3 to 3.0 hrs) and for cedazuridine was 3 hrs (range 1.5 to 6.1 hrs).8
The bioavailability of decitabine, as assessed by comparing the AUC of oral decitabine co-administered with cedazuridine to intravenous decitabine alone, was 60% on day 1 (90% CI of 55-65%). The corresponding values on day 5 and considering the cumulative day 5 dose were 106% (90% CI: 98, 114) and 99% (90% CI: 93, 106). Hence, the oral bioavailability of decitabine approaches 100% over the 5-day treatment cycle.8
- Volume of distribution
The apparent volume of distribution (and coefficient of variation) of decitabine and cedazuridine at steady state was 417 (54%) and 296 (51%), respectively.8
- Protein binding
Neither decitabine nor cedazuridine display extensive plasma protein binding. The bound fraction of decitabine between doses of 17 and 342 ng/mL was between 4 and 6%, while that of cedazuridine for doses between 1000 ng/mL and 50000 ng/mL was between 34 and 38%.8
- Metabolism
The metabolism of cedazuridine is not well-established. Cedazuridine is known to be converted to an epimer that is roughly 10-fold less effective in inhibiting cytidine deaminase and is subsequently degraded through unknown pathways.4,8
Hover over products below to view reaction partners
- Route of elimination
Roughly 46% of cedazuridine is found in urine, 21% of which is unchanged, and 51% is found in feces, 27% of which is unchanged.8
- Half-life
Cedazuridine has a steady-state half-life of 6.7 hours, with a coefficient of variation of 19%.8
- Clearance
Cedazuridine has an apparent steady-state clearance of 30.3 L/hours, with a coefficient of variation of 46%.8
- Adverse Effects
Improve decision support & research outcomesWith structured adverse effects data, including: blackbox warnings, adverse reactions, warning & precautions, & incidence rates.Improve decision support & research outcomes with our structured adverse effects data.- Toxicity
Cedazuridine administered orally to mice in 7 days on/21 days off cycles for a total of 91 days in doses of 100, 300, or 1000 mg/kg produced abnormal effects only at the 1000 mg/kg dose, which is roughly 108 times the recommended dose in humans. These effects included abnormal histology of the testes, epididymis, and ovaries, as well as decreased sperm count; these effects were reversible following cedazuridine removal.
- 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.
Drug Interaction Integrate drug-drug
interactions in your softwareAzacitidine The serum concentration of Azacitidine can be increased when it is combined with Cedazuridine. Capecitabine The serum concentration of Capecitabine can be increased when it is combined with Cedazuridine. Cytarabine The serum concentration of Cytarabine can be increased when it is combined with Cedazuridine. Gemcitabine The serum concentration of Gemcitabine can be increased when it is combined with Cedazuridine. 
Identify potential medication risksEasily compare up to 40 drugs with our drug interaction checker.Get severity rating, description, and management advice.Learn more - Food Interactions
- Take on an empty stomach. Avoid consuming food for both two hours before and after each dose.
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.- Mixture Products
Name Ingredients Dosage Route Labeller Marketing Start Marketing End Region Image Inqovi Cedazuridine (100 mg) + Decitabine (35 mg) Tablet Oral Otsuka Pharmaceutical Co., Ltd. 2020-11-11 Not applicable Canada 
Inqovi Cedazuridine (100 mg/1) + Decitabine (35 mg/1) Tablet, film coated Oral Taiho Pharmaceutical Co., Ltd. 2020-07-07 Not applicable US 
Categories
- Drug Categories
- Classification
- Not classified
- Affected organisms
- Humans and other mammals
Chemical Identifiers
- UNII
- 39IS23Q1EW
- CAS number
- 1141397-80-9
- InChI Key
- VUDZSIYXZUYWSC-DBRKOABJSA-N
- InChI
- InChI=1S/C9H14F2N2O5/c10-9(11)6(16)4(3-14)18-7(9)13-2-1-5(15)12-8(13)17/h4-7,14-16H,1-3H2,(H,12,17)/t4-,5-,6-,7-/m1/s1
- IUPAC Name
- (4R)-1-[(2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-4-hydroxy-1,3-diazinan-2-one
- SMILES
- OC[C@H]1O[C@@H](N2CC[C@@H](O)NC2=O)C(F)(F)[C@@H]1O
References
- Synthesis Reference
Ferraris D, Duvall B, Delahanty G, Mistry B, Alt J, Rojas C, Rowbottom C, Sanders K, Schuck E, Huang KC, Redkar S, Slusher BB, Tsukamoto T: Design, synthesis, and pharmacological evaluation of fluorinated tetrahydrouridine derivatives as inhibitors of cytidine deaminase. J Med Chem. 2014 Mar 27;57(6):2582-8. doi: 10.1021/jm401856k. Epub 2014 Feb 24.
- General References
- Kennedy JA, Ebert BL: Clinical Implications of Genetic Mutations in Myelodysplastic Syndrome. J Clin Oncol. 2017 Mar 20;35(9):968-974. doi: 10.1200/JCO.2016.71.0806. Epub 2017 Feb 13. [Article]
- Gill H, Leung AY, Kwong YL: Molecular and Cellular Mechanisms of Myelodysplastic Syndrome: Implications on Targeted Therapy. Int J Mol Sci. 2016 Mar 24;17(4):440. doi: 10.3390/ijms17040440. [Article]
- Hasserjian RP: Myelodysplastic Syndrome Updated. Pathobiology. 2019;86(1):7-13. doi: 10.1159/000489702. Epub 2018 Jul 24. [Article]
- Ferraris D, Duvall B, Delahanty G, Mistry B, Alt J, Rojas C, Rowbottom C, Sanders K, Schuck E, Huang KC, Redkar S, Slusher BB, Tsukamoto T: Design, synthesis, and pharmacological evaluation of fluorinated tetrahydrouridine derivatives as inhibitors of cytidine deaminase. J Med Chem. 2014 Mar 27;57(6):2582-8. doi: 10.1021/jm401856k. Epub 2014 Feb 24. [Article]
- Savona MR, Odenike O, Amrein PC, Steensma DP, DeZern AE, Michaelis LC, Faderl S, Harb W, Kantarjian H, Lowder J, Oganesian A, Azab M, Garcia-Manero G: An oral fixed-dose combination of decitabine and cedazuridine in myelodysplastic syndromes: a multicentre, open-label, dose-escalation, phase 1 study. Lancet Haematol. 2019 Apr;6(4):e194-e203. doi: 10.1016/S2352-3026(19)30030-4. [Article]
- Garcia-Manero G, Griffiths EA, Steensma DP, Roboz GJ, Wells RA, McCloskey J, Odenike O, DeZern A, Yee K, Busque L, O'Connell C, Michaelis LC, Brandwein J, Kantarjian HM, Oganesian A, Azab M, Savona MR: Oral cedazuridine/decitabine: a phase 2, pharmacokinetic/pharmacodynamic, randomized, crossover study in MDS and CMML. Blood. 2020 Apr 13. pii: 454379. doi: 10.1182/blood.2019004143. [Article]
- Duchmann M, Itzykson R: Clinical update on hypomethylating agents. Int J Hematol. 2019 Aug;110(2):161-169. doi: 10.1007/s12185-019-02651-9. Epub 2019 Apr 24. [Article]
- FDA Approved Drug Products: INQOVI (decitabine and cedazuridine) oral tablets [Link]
- External Links
- ChemSpider
- 34236147
- 2384449
- ChEMBL
- CHEMBL3237547
- ZINC
- ZINC000043205136
- Wikipedia
- Decitabine/cedazuridine
Clinical Trials
- Clinical Trials
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Tablet Oral Tablet, film coated Oral - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US8618075 No 2013-12-31 2028-10-16 US US8268800 No 2012-09-18 2030-08-22 US US9567363 No 2017-02-14 2028-10-16 US
Properties
- State
- Solid
- Experimental Properties
Property Value Source melting point (°C) 162-165 Ferraris D, Duvall B, Delahanty G, Mistry B, Alt J, Rojas C, Rowbottom C, Sanders K, Schuck E, Huang KC, Redkar S, Slusher BB, Tsukamoto T: Design, synthesis, and pharmacological evaluation of fluorinated tetrahydrouridine derivatives as inhibitors of cytidine deaminase. J Med Chem. 2014 Mar 27;57(6):2582-8. doi: 10.1021/jm401856k. Epub 2014 Feb 24. - Predicted Properties
Property Value Source Water Solubility 182.0 mg/mL ALOGPS logP -0.64 ALOGPS logP -1.4 Chemaxon logS -0.17 ALOGPS pKa (Strongest Acidic) 11 Chemaxon pKa (Strongest Basic) -3 Chemaxon Physiological Charge 0 Chemaxon Hydrogen Acceptor Count 5 Chemaxon Hydrogen Donor Count 4 Chemaxon Polar Surface Area 102.26 Å2 Chemaxon Rotatable Bond Count 2 Chemaxon Refractivity 51.75 m3·mol-1 Chemaxon Polarizability 22.71 Å3 Chemaxon Number of Rings 2 Chemaxon Bioavailability 1 Chemaxon Rule of Five Yes Chemaxon Ghose Filter No Chemaxon Veber's Rule No Chemaxon MDDR-like Rule No Chemaxon - Predicted ADMET Features
- Not Available
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
- Not Available
Targets
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- General Function
- Zinc ion binding
- Specific Function
- This enzyme scavenges exogenous and endogenous cytidine and 2'-deoxycytidine for UMP synthesis.
- Gene Name
- CDA
- Uniprot ID
- P32320
- Uniprot Name
- Cytidine deaminase
- Molecular Weight
- 16184.545 Da
References
- Ferraris D, Duvall B, Delahanty G, Mistry B, Alt J, Rojas C, Rowbottom C, Sanders K, Schuck E, Huang KC, Redkar S, Slusher BB, Tsukamoto T: Design, synthesis, and pharmacological evaluation of fluorinated tetrahydrouridine derivatives as inhibitors of cytidine deaminase. J Med Chem. 2014 Mar 27;57(6):2582-8. doi: 10.1021/jm401856k. Epub 2014 Feb 24. [Article]
- FDA Approved Drug Products: INQOVI (decitabine and cedazuridine) oral tablets [Link]
Drug created at July 09, 2020 18:25 / Updated at August 19, 2021 10:28