Cedazuridine

Identification

Name
Cedazuridine
Accession Number
DB15694
Description

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
Thumb
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

Pharmacology
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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

Associated Conditions
Contraindications & Blackbox Warnings
Contraindications
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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

TargetActionsOrganism
ACytidine deaminase
inhibitor
Humans
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 appreciable plasma protein binding. The bound fraction of decitabine between doses of 17 and 342 ng/mL was between 2 and 4%, while that of cedazuridine for doses between 1000 ng/mL and 50000 ng/mL was between 2 and 6%.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

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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
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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.

Affected organisms
  • Humans and other mammals
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
AzacitidineThe serum concentration of Azacitidine can be increased when it is combined with Cedazuridine.
CapecitabineThe serum concentration of Capecitabine can be increased when it is combined with Cedazuridine.
CytarabineThe serum concentration of Cytarabine can be increased when it is combined with Cedazuridine.
GemcitabineThe serum concentration of Gemcitabine can be increased when it is combined with Cedazuridine.
Interactions
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Food Interactions
  • Take on an empty stomach. Avoid consuming food for both two hours before and after each dose.

Products

Products
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Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing EndRegionImage
InqoviCedazuridine (100 mg/1) + Decitabine (35 mg/1)Tablet, film coatedOralTaiho Pharmaceutical Co., Ltd.2020-07-07Not applicableUS flag
InqoviCedazuridine (100 mg) + Decitabine (35 mg)TabletOralOtsuka Pharmaceutical Co., Ltd.2020-11-11Not applicableCanada flag

Categories

Drug Categories
Classification
Not classified

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
  1. 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. [PubMed:28297619]
  2. 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. [PubMed:27023522]
  3. Hasserjian RP: Myelodysplastic Syndrome Updated. Pathobiology. 2019;86(1):7-13. doi: 10.1159/000489702. Epub 2018 Jul 24. [PubMed:30041243]
  4. 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. [PubMed:24520856]
  5. 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. [PubMed:30926081]
  6. 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. [PubMed:32285126]
  7. 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. [PubMed:31020568]
  8. FDA Approved Drug Products: INQOVI (decitabine and cedazuridine) oral tablets [Link]
ChemSpider
34236147
RxNav
2384449
ChEMBL
CHEMBL3237547
ZINC
ZINC000043205136

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3RecruitingTreatmentAcute Myeloid Leukemia (AML) / Chronic Myelomonocytic Leukemia / Myelodysplastic Syndromes (MDS)1
2Enrolling by InvitationTreatmentAcute Myeloid Leukemia (AML) / Chronic Myelomonocytic Leukemia / Myelodysplastic Syndromes (MDS)1
2, 3RecruitingTreatmentAcute Myeloid Leukemia (AML) / Chronic Myeloid Leukemia (CML) / Myelodysplastic Syndrome/Neoplasm / Myelodysplastic Syndromes (MDS)1
1CompletedBasic ScienceAcute Myeloid Leukemia (AML) / Chronic Myelomonocytic Leukemia / Myelodysplastic Syndromes (MDS)1
1Not Yet RecruitingTreatmentAcute Myeloid Leukemia (AML)1
1RecruitingOtherTumors, Solid1
1RecruitingTreatmentAcute Myeloid Leukemia (AML)1
1RecruitingTreatmentMyelodysplastic Syndromes (MDS)1
1, 2CompletedTreatmentMDS / Myelodysplastic Syndrome1
1, 2Not Yet RecruitingTreatmentChronic Myelomonocytic Leukemia / Myelodysplastic Syndrome1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
TabletOral
Tablet, film coatedOral
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US8618075No2008-10-162028-10-16US flag
US8268800No2010-08-222030-08-22US flag
US9567363No2008-10-162028-10-16US flag

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)162-165Ferraris 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
PropertyValueSource
Water Solubility182.0 mg/mLALOGPS
logP-0.64ALOGPS
logP-1.4ChemAxon
logS-0.17ALOGPS
pKa (Strongest Acidic)11ChemAxon
pKa (Strongest Basic)-3ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count4ChemAxon
Polar Surface Area102.26 Å2ChemAxon
Rotatable Bond Count2ChemAxon
Refractivity51.75 m3·mol-1ChemAxon
Polarizability22.71 Å3ChemAxon
Number of Rings2ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
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
  1. 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. [PubMed:24520856]
  2. FDA Approved Drug Products: INQOVI (decitabine and cedazuridine) oral tablets [Link]

Drug created on July 09, 2020 18:25 / Updated on February 21, 2021 18:55