Decitabine and cedazuridine
Decitabine and cedazuridine Uses, Dosage, Side Effects, Food Interaction and all others data.
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 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.
Myelodysplastic syndromes (MDS) are a heterogeneous group of hematopoietic neoplasms with variable underlying etiology and presentation, including neutropenia and thrombocytopenia. Further mutations leading to increased proliferation of cancerous cells can eventually lead to secondary acute myeloid leukemia, which has a poor prognosis. Among treatment options, nucleoside analogues such as decitabine and azacitidine integrate into cellular DNA and inhibit the action of DNA methyltransferases, leading to global hypomethylation and related downstream therapeutic benefits.
Decitabine was developed by MGI Pharma/SuperGen Inc. and was approved by the FDA for the treatment of MDS on February 5, 2006. It was first marketed under the name Dacogen®. It is also available as an oral combination product together with the cytidine deaminase inhibitor cedazuridine.
Decitabine is a prodrug analogue of the natural nucleotide 2’-deoxycytidine, which, upon being phosphorylated intracellularly, is incorporated into DNA and exerts numerous effects on gene expression. The use of decitabine is associated with neutropenia and thrombocytopenia. In addition, decitabine can cause fetal harm in pregnant women; effective contraception and avoidance of pregnancy are recommended during treatment with decitabine.
| Trade Name | Decitabine and cedazuridine |
| Generic | Cedazuridine + decitabine |
| Type | Oral |
| Therapeutic Class | |
| Manufacturer | |
| Available Country | United States |
| Last Updated: | September 19, 2023 at 7:00 am |
Uses
Cedazuridine is a cytidine deaminase inhibitor coadministered with the hypomethylating agent decitabine for the treatment of variable forms of myelodysplastic syndrome (MDS).
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).
Decitabine is a chemotherapeutic pyrimidine nucleoside analogue used for the treatment of myelodysplastic syndromes (MDS) by inducing DNA hypomethylation and corresponding alterations in gene expression.
Decitabine is indicated for the treatment of patients with myelodysplastic syndromes (MDS) including all French-American-British subtypes (refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and chronic myelomonocytic leukemia), as well as for MDS scored as belonging to the intermediate-1, intermediate-2, or high-risk group in the International Prognostic Scoring System.
Decitabine and cedazuridine is also used to associated treatment for these conditions: Chronic Myelomonocytic Leukemia, Myelodysplastic Syndromes (MDS)Chronic Myelomonocytic Leukemia, Myelodysplastic Syndromes (MDS)
How Decitabine and cedazuridine works
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.
Myelodysplastic syndromes (MDS) are a group of hematopoietic neoplasms that manifest in peripheral cytopenias and may eventually progress to secondary acute myeloid leukemia (sAML). Included in the over 45 genes commonly mutated in MDS patients are those involved in DNA methylation and histone modification, and it is well-established that alteration of the epigenetic landscape is a feature of myeloid leukemias.
Decitabine is considered a prodrug, as it requires transport into cells and subsequent phosphorylation by distinct kinases to generate the active molecule 5-aza-2'-deoxycytidine-triphosphate, which is incorporated by DNA polymerase during DNA replication. Once incorporated into DNA, decitabine is recognized as a substrate by DNA methyltransferase enzymes (DNMTs), specifically DNMT1, but due to the presence of an N5 rather than C5 atom, traps the DNMT through the irreversible formation of a covalent bond. At low concentrations, this mode of action depletes DNMTs and results in global DNA hypomethylation while at high concentrations, it additionally results in double-strand breaks and cell death.
The general hypothesis regarding decitabine's therapeutic efficacy is that the global hypomethylation it induces results in the expression of previously silent tumour suppressor genes. However, there are other putative mechanisms also related to this change in DNA methylation, including indirect alteration of transcription through effects on transcription factors, indirectly altering histone modifications and chromatin structure, and activating pathways involved in DNA damage response. The overall effect of decitabine is a decrease in neoplastic cell proliferation and an increase in the expression of tumour suppressor genes.
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.
Decitabine has demonstrated mutagenic potential in L5178Y mouse lymphoma cells and an Escherichia coil lac-I transgene within the colonic DNA of mice. Decitabine treatment increased chromosomal rearrangements in fruit fly larvae. In mouse models, decitabine exposure in utero (approximately 7% of the recommended daily dose) resulted in decreased weight and decreased male fertility. Adult male mice administered with between 0.3 and 1% of the recommended daily dose of decitabine three times a week for seven weeks had smaller testes with abnormal histology, decreased sperm count, and decreased fertility.
There is no known antidote for decitabine overdose. Patients experiencing an overdose are at an increased risk of severe adverse effects such as myelosuppression, including prolonged and severe neutropenia and thrombocytopenia. Symptomatic and supportive measures are recommended.
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.
Decitabine as an apparent volume of distribution of 4.59 ± 1.42 L/kg.
Elimination Route
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.
Decitabine administered intravenously at 15 mg/m2 for three hours every eight hours over three days resulted in a Cmax of 73.8 ng/mL (66% coefficient of variation, CV), an AUC0-∞ of 163 ng*h/mL (62% CV), and a cumulative AUC of 1332 ng*h/mL (95% CI of 1010-1730).
Similarly, decitabine at 20 mg/m2
Half Life
Cedazuridine has a steady-state half-life of 6.7 hours, with a coefficient of variation of 19%.
Decitabine has a half-life of 0.62 hours (49% CV) when administered intravenously at 15 mg/m2 for three hours every eight hours over three days, and a half-life of 0.54 hours (43% CV) at 20 mg/m2 for one hour once daily over five days.
Clearance
Cedazuridine has an apparent steady-state clearance of 30.3 L/hours, with a coefficient of variation of 46%.
Decitabine has a clearance of 125 L/hr/m2 (53% CV) when administered intravenously at 15 mg/m2 for three hours every eight hours over three days, and a clearance of 210 L/hr/m2 (47% CV) at 20 mg/m2 for one hour once daily over five days.
Elimination Route
Roughly 46% of cedazuridine is found in urine, 21% of which is unchanged, and 51% is found in feces, 27% of which is unchanged.
Less than 1% of administered decitabine is excreted in the urine.
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