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1. (4r)-2'-deoxy-2',2'-difluoro-3,4,5,6-tetrahydrouridine
1. 1141397-80-9
2. Cedazuridine [inn]
3. Cedazuridine [usan]
4. 39is23q1ew
5. Chembl3237547
6. E7727
7. Astx727 Component Cedazuridine
8. Astx-727 Component Cedazuridine
9. (4r)-2'-deoxy-2',2'-difluoro-3,4,5,6-tetrahydrouridine
10. E-7727
11. (4r)-1-[(2r,4r,5r)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-4-hydroxy-1,3-diazinan-2-one
12. Uridine, 2'-deoxy-2',2'-difluoro-3,4,5,6-tetrahydro-, (4r)-
13. (r)-1-((2r,4r,5r)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-4-hydroxytetrahydropyrimidin-2(1h)-one
14. Cedazuridine [usan:inn]
15. Unii-39is23q1ew
16. Cedazuridine [who-dd]
17. Schembl172256
18. Gtpl11101
19. Cedazuridine [orange Book]
20. Ex-a5549
21. Inqovi Component Cedazuridine
22. Bdbm50007029
23. Who 10741
24. Astx727 (cedazuridine + Decitabine)
25. At22227
26. Cedazuridine Component Of Inqovi
27. Compound 7a [pmid: 24520856]
28. A937507
29. (4r)-4-hydroxy-1-(2,2-difluoro-2-deoxy-beta-d-ribofuranosyl)-3,4,5,6-tetrahydropyrimidine-2(1h)-one
| Molecular Weight | 268.21 g/mol |
|---|---|
| Molecular Formula | C9H14F2N2O5 |
| XLogP3 | -1.1 |
| Hydrogen Bond Donor Count | 4 |
| Hydrogen Bond Acceptor Count | 7 |
| Rotatable Bond Count | 2 |
| Exact Mass | 268.08707788 g/mol |
| Monoisotopic Mass | 268.08707788 g/mol |
| Topological Polar Surface Area | 102 Ų |
| Heavy Atom Count | 18 |
| Formal Charge | 0 |
| Complexity | 343 |
| Isotope Atom Count | 0 |
| Defined Atom Stereocenter Count | 4 |
| Undefined Atom Stereocenter Count | 0 |
| Defined Bond Stereocenter Count | 0 |
| Undefined Bond Stereocenter Count | 0 |
| Covalently Bonded Unit Count | 1 |
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).
Cedazuridine is a cytidine deaminase inhibitor that is co-administered with hypomethylating agents such as [decitabine] in order to increase their oral bioavailability. In combination with hypomethylating agents, cedazuridine may cause myelosuppression and embryo-fetal toxicity and should be administered with appropriate monitoring.
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). 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.
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.
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.
Clearance
Cedazuridine has an apparent steady-state clearance of 30.3 L/hours, with a coefficient of variation of 46%.
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.
Cedazuridine has a steady-state half-life of 6.7 hours, with a coefficient of variation of 19%.
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. 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. 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. Co-administration with cedazuridine, which is an efficient inhibitor of cytidine deaminase, drastically increases the oral bioavailability of [decitabine], allowing for combination oral therapy.
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