Peringatan Keamanan

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.

Cedazuridine

DB15694

small molecule approved investigational

Deskripsi

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.A215082, A215092, A215097 Hypomethylating agents such as decitabine and azacitidine are used to treat MDS through inducing DNA hypomethylation and apoptosis of cancerous cells.A215127, L14897 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.A215107, A215112, A215117, A215127 Cedazuridine is a fluorinated tetrahydrouridine derivative specifically designed to inhibit CDA and facilitate oral administration of hypomethylating agents.A215107, A215112, A215117, A215127, L14897

Cedazuridine was first reported in 2014,A215107 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®.L14897

Struktur Molekul 2D

Berat 268.217
Wujud solid

Peta Jejaring Molekuler
Legenda: Obat • Target • Gen • Enzim • (Panah → menunjukkan arah efek / relasi) • Transporter • Carrier

Profil Farmakokinetik

Waktu Paruh (Half-Life) Cedazuridine has a steady-state half-life of 6.7 hours, with a coefficient of variation of 19%.[L14897]
Volume Distribusi The apparent volume of distribution (and coefficient of variation) of [decitabine] and cedazuridine at steady state was 417 (54%) and 296 (51%), respectively.[L14897]
Klirens (Clearance) Cedazuridine has an apparent steady-state clearance of 30.3 L/hours, with a coefficient of variation of 46%.[L14897]

Absorpsi

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).L14897 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.L14897

Metabolisme

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.A215107, L14897

Rute Eliminasi

Roughly 46% of cedazuridine is found in urine, 21% of which is unchanged, and 51% is found in feces, 27% of which is unchanged.L14897

Interaksi Makanan

1 Data
  • 1. Take on an empty stomach. Avoid consuming food for both two hours before and after each dose.

Interaksi Obat

4 Data
Azacitidine The serum concentration of Azacitidine can be increased when it is combined with Cedazuridine.
Cytarabine The serum concentration of Cytarabine can be increased when it is combined with Cedazuridine.
Capecitabine The serum concentration of Capecitabine can be increased when it is combined with Cedazuridine.
Gemcitabine The serum concentration of Gemcitabine can be increased when it is combined with Cedazuridine.

Target Protein

Cytidine deaminase CDA

Referensi & Sumber

Synthesis reference: Ferraris D, Duvall B, Delahanty G, Mistry B, Alt J, Rojas C, Rowbottom C, Sanders K, Schuck E, Huang KC, Redkar S, Slusher BB, Tsukamoto T: Design, synthesis, and pharmacological evaluation of fluorinated tetrahydrouridine derivatives as inhibitors of cytidine deaminase. J Med Chem. 2014 Mar 27;57(6):2582-8. doi: 10.1021/jm401856k. Epub 2014 Feb 24.
Artikel (PubMed)
  • PMID: 28297619
    Kennedy JA, Ebert BL: Clinical Implications of Genetic Mutations in Myelodysplastic Syndrome. J Clin Oncol. 2017 Mar 20;35(9):968-974. doi: 10.1200/JCO.2016.71.0806. Epub 2017 Feb 13.
  • PMID: 27023522
    Gill H, Leung AY, Kwong YL: Molecular and Cellular Mechanisms of Myelodysplastic Syndrome: Implications on Targeted Therapy. Int J Mol Sci. 2016 Mar 24;17(4):440. doi: 10.3390/ijms17040440.
  • PMID: 30041243
    Hasserjian RP: Myelodysplastic Syndrome Updated. Pathobiology. 2019;86(1):7-13. doi: 10.1159/000489702. Epub 2018 Jul 24.
  • PMID: 24520856
    Ferraris D, Duvall B, Delahanty G, Mistry B, Alt J, Rojas C, Rowbottom C, Sanders K, Schuck E, Huang KC, Redkar S, Slusher BB, Tsukamoto T: Design, synthesis, and pharmacological evaluation of fluorinated tetrahydrouridine derivatives as inhibitors of cytidine deaminase. J Med Chem. 2014 Mar 27;57(6):2582-8. doi: 10.1021/jm401856k. Epub 2014 Feb 24.
  • PMID: 30926081
    Savona MR, Odenike O, Amrein PC, Steensma DP, DeZern AE, Michaelis LC, Faderl S, Harb W, Kantarjian H, Lowder J, Oganesian A, Azab M, Garcia-Manero G: An oral fixed-dose combination of decitabine and cedazuridine in myelodysplastic syndromes: a multicentre, open-label, dose-escalation, phase 1 study. Lancet Haematol. 2019 Apr;6(4):e194-e203. doi: 10.1016/S2352-3026(19)30030-4.
  • PMID: 32285126
    Garcia-Manero G, Griffiths EA, Steensma DP, Roboz GJ, Wells RA, McCloskey J, Odenike O, DeZern A, Yee K, Busque L, O'Connell C, Michaelis LC, Brandwein J, Kantarjian HM, Oganesian A, Azab M, Savona MR: Oral cedazuridine/decitabine: a phase 2, pharmacokinetic/pharmacodynamic, randomized, crossover study in MDS and CMML. Blood. 2020 Apr 13. pii: 454379. doi: 10.1182/blood.2019004143.
  • PMID: 31020568
    Duchmann M, Itzykson R: Clinical update on hypomethylating agents. Int J Hematol. 2019 Aug;110(2):161-169. doi: 10.1007/s12185-019-02651-9. Epub 2019 Apr 24.

Contoh Produk & Brand

Produk: 3 • International brands: 0
Produk
  • Inaqovi
    Tablet, film coated • - • Oral • EU • Approved
  • Inqovi
    Tablet • - • Oral • Canada • Approved
  • Inqovi
    Tablet, film coated • - • Oral • US • Approved

Sekuens Gen/Protein (FASTA)

Sekuens dimuat saat dibutuhkan agar halaman tetap ringan.
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