Natdecita

Uses

Natdecita is a chemotherapeutic pyrimidine nucleoside analogue used for the treatment of myelodysplastic syndromes (MDS) by inducing DNA hypomethylation and corresponding alterations in gene expression.

Natdecita 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.

Natdecita is also used to associated treatment for these conditions: Chronic Myelomonocytic Leukemia, Myelodysplastic Syndromes (MDS)

How Natdecita works

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.

Natdecita 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

Natdecita has demonstrated mutagenic potential in L5178Y mouse lymphoma cells and an Escherichia coil lac-I transgene within the colonic DNA of mice. Natdecita 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.

Food Interaction

Natdecita Drug Interaction

Unknown: aminocaproic acid, aminocaproic acid, diphenhydramine, diphenhydramine, loratadine, loratadine, docusate, docusate, prochlorperazine, prochlorperazine, bisacodyl, bisacodyl, acetaminophen, acetaminophen, venetoclax, venetoclax, alprazolam, alprazolam, ondansetron, ondansetron

Natdecita Disease Interaction

Moderate: liver impairment, hematological toxicity, renal dysfunction

Volume of Distribution

Natdecita as an apparent volume of distribution of 4.59 ± 1.42 L/kg.

Elimination Route

Natdecita administered intravenously at 15 mg/m² for three hours every eight hours over three days resulted in a C_max of 73.8 ng/mL (66% coefficient of variation, CV), an AUC_0-∞ 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

Natdecita 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

Natdecita 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

Less than 1% of administered decitabine is excreted in the urine.

Innovators Monograph

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