Cedazuridine (compound 7a) exhibits superior acid stability [1]. Cedazuridine (0-10 μM; 72 h) does not amplify AZA (5-Azacytidine)'s growth-inhibitory action on AML cell lines [2].

In mouse MOLM-13 CDX and PDX models, Chidazuridine (3 mg/kg; oral; once daily for 7 days) plus 2.5 mg/kg AZA led to tumor remission [2].

Animal/Disease Models: Female NSGS mice, 6-8 weeks old, human cell line-derived (CDX) and primary patient-derived xenograft (PDX) models [2]
Doses: 3 mg/kg
Route of Administration: Orally, with 2.5 mg combination/kg AZA one time/day for 7 days
Experimental Results: Combination with AZA reduces leukemic expansion in cell line-derived xenografts and demonstrates preliminary safety and efficacy in PDX model of primary AML sex.

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Animal/Disease Models: NSGS male mice [2]
Doses: 1, 3, 10 and 30 mg/kg
Route of Administration: po (po (oral gavage)) combined with 2.5 mg/kg AZA (pharmacokinetic/PK/PK study)
Experimental Results: The AUC of oral AZA was There was a dose-dependent increase and in comparison with standard ip AZA doses.

Absorption, Distribution and Excretion
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.
Roughly 46% of cedazuridine is found in urine, 21% of which is unchanged, and 51% is found in feces, 27% of which is unchanged.
The apparent volume of distribution (and coefficient of variation) of [decitabine] and cedazuridine at steady state was 417 (54%) and 296 (51%), respectively.
Cedazuridine has an apparent steady-state clearance of 30.3 L/hours, with a coefficient of variation of 46%.

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Metabolism / Metabolites
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.

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Biological Half-Life
Cedazuridine has a steady-state half-life of 6.7 hours, with a coefficient of variation of 19%.

Hepatotoxicity
In the preregistration trials of the combination of decitabine and cedazuridine, serum aminotransferase elevations occurred in 20% to 37% of patients but were invariably transient and usually mild. ALT elevations above 5 times the upper limit of normal arose in 1% to 3% of patients and usually resolved promptly with dose adjustment or discontinuation. Several patients, however, developed ALT elevations accompanied by increases in serum bilirubin, but in all instances other causes appeared to be responsible, such as sepsis, pancreatitis and myocarditis. With more widespread clinical use after its approval, there have been no published reports of clinically apparent liver injury attributed to the combination of cedazuridine and decitabine.
Likelihood score: E* (suspected but unproven rare cause of clinically apparent liver injury).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Cedazuridine is used in a combination product with decitabine. Most sources consider breastfeeding to be contraindicated during maternal antineoplastic drug therapy. It might be possible to breastfeed safely during intermittent cedazuridine-decitabine therapy with an appropriate period of breastfeeding abstinence. The manufacturer recommends an abstinence period of 2 weeks after the last dose of the cedazuridine-decitabine combination. Chemotherapy may adversely affect the normal microbiome and chemical makeup of breastmilk. Women who receive chemotherapy during pregnancy are more likely to have difficulty nursing their infant.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
A telephone follow-up study was conducted on 74 women who received cancer chemotherapy at one center during the second or third trimester of pregnancy to determine if they were successful at breastfeeding postpartum. Only 34% of the women were able to exclusively breastfeed their infants, and 66% of the women reported experiencing breastfeeding difficulties. This was in comparison to a 91% breastfeeding success rate in 22 other mothers diagnosed during pregnancy, but not treated with chemotherapy. Other statistically significant correlations included: 1) mothers with breastfeeding difficulties had an average of 5.5 cycles of chemotherapy compared with 3.8 cycles among mothers who had no difficulties; and 2) mothers with breastfeeding difficulties received their first cycle of chemotherapy on average 3.4 weeks earlier in pregnancy. Of the 9 women who received a fluorouracil-containing regimen, 8 had breastfeeding difficulties.

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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%.

[1]. Ferraris D, et al. Design, synthesis, and pharmacological evaluation of fluorinated tetrahydrouridine derivatives as inhibitors of cytidine deaminase. J Med Chem. 2014 Mar 27; 57(6):2582-8.
[2]. Ramsey H E, et al. Oral azacitidine and cedazuridine approximate parenteral azacitidine efficacy in murine model. Targeted Oncology, 2020, 15(2): 231-240.

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. Hypomethylating agents such as [decitabine] and [azacitidine] are used to treat MDS through inducing DNA hypomethylation and apoptosis of cancerous cells. 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. Cedazuridine is a fluorinated tetrahydrouridine derivative specifically designed to inhibit CDA and facilitate oral administration of hypomethylating agents. Cedazuridine was first reported in 2014, 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®.
Cedazuridine is a small molecule inhibitor of cytidine deaminase that is used as a pharmacoenhancer of decitabine to increase oral bioavailability of this DNA methylase inhibitor treatment of myelodysplastic syndromes. The combination of oral decitabine and cedazuridine is associated with a low rate of minor serum enzyme elevations during therapy that is usually attributed to decitabine. The oral combination has not been linked to cases of clinically apparent liver injury.
Cedazuridine is an orally available synthetic nucleoside analog derived from tetrahydrouridine (THU) and cytidine deaminase inhibitor (CDAi), that can potentially be used to prevent the breakdown of cytidines. Upon oral administration, cedazuridine binds to and inhibits CDA, an enzyme primarily found in the gastrointestinal (GI) tract and liver that catalyzes the deamination of cytidine and cytidine analogs. Given in combination with a cytidine, such as the antineoplastic hypomethylating agent decitabine, it specifically prevents its breakdown and increases its bioavailability and efficacy. In addition, this allows for lower doses of decitabine to be administered, which results in decreased decitabine-associated GI toxicity.

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Drug 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).

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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. 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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Pharmacodynamics
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.

C9H14F2N2O5

268.214669704437

268.087

1141397-80-9

Cedazuridine hydrochloride

25267009

Typically exists as solid at room temperature

162-165

-1.1

4

7

2

18

343

4

C1CN(C(=O)N[C@@H]1O)[C@H]2C([C@@H]([C@H](O2)CO)O)(F)F

VUDZSIYXZUYWSC-DBRKOABJSA-N

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

(R)-1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-4-hydroxytetrahydropyrimidin-2(1H)-one

WHO 10741 E7727 WHO-10741 E-7727WHO10741 E 7727

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: This product requires protection from light (avoid light exposure) during transportation and storage.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~50 mg/mL (~186.42 mM)

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)