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General Description:

Cedazuridine, identified by CAS number 1141397-80-9, is a notable compound with significant therapeutic applications. 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 and 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 for sale by Astex Pharmaceuticals Inc under the name INQOVI®.

Indications:

This drug is primarily indicated for: 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). Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Cedazuridine undergoes metabolic processing primarily in: 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. This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Cedazuridine are crucial for its therapeutic efficacy: Cedazuridine (100 mg) taken orally with (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 and 2950 (49%) and 3291 (45%) ng\*hr/mL for cedazuridine, respectively. Overall, the 5-day cumulative AUC for was 851 (50%). Similarly, the C_max for and cedazuridine was 145 (55%) and 371 (52%) ng/mL, respectively. The median T_max for 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 , as assessed by comparing the AUC of oral co-administered with cedazuridine to intravenous 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 approaches 100% over the 5-day treatment cycle. The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Cedazuridine is an important consideration for its dosing schedule: Cedazuridine has a steady-state half-life of 6.7 hours, with a coefficient of variation of 19%. This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Cedazuridine exhibits a strong affinity for binding with plasma proteins: Neither nor cedazuridine display extensive plasma protein binding. The bound fraction of 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%. This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Cedazuridine from the body primarily occurs through: Roughly 46% of cedazuridine is found in urine, 21% of which is unchanged, and 51% is found in feces, 27% of which is unchanged. Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Cedazuridine is distributed throughout the body with a volume of distribution of: The apparent volume of distribution (and coefficient of variation) of and cedazuridine at steady state was 417 (54%) and 296 (51%), respectively. This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Cedazuridine is a critical factor in determining its safe and effective dosage: Cedazuridine has an apparent steady-state clearance of 30.3 L/hours, with a coefficient of variation of 46%. It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Cedazuridine exerts its therapeutic effects through: Cedazuridine is a cytidine deaminase inhibitor that is co-administered with hypomethylating agents such as 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. The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Cedazuridine functions by: 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 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 , allowing for combination oral therapy. This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Categories:

Cedazuridine is categorized under the following therapeutic classes: Cytidine Deaminase, antagonists & inhibitors, Nucleic Acids, Nucleotides, and Nucleosides, Nucleosides, Pyrimidine Nucleosides, Pyrimidines, Ribonucleosides. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.

Experimental Properties:

Further physical and chemical characteristics of Cedazuridine include:

• Melting Point: 162-165