Omacetaxine mepesuccinate

Omacetaxine mepesuccinate
Clinical data
Trade names Synribo
AHFS/Drugs.com Monograph
License data
Pregnancy
category
  • US: D (Evidence of risk)
    Routes of
    administration    		 Subcutaneous, intravenous infusion
    ATC code
    Legal status
    Legal status
    Pharmacokinetic data
    Protein binding 50%
    Metabolism Mostly via plasma esterases
    Elimination half-life 6 hours
    Excretion Urine (≤15% unchanged)
    Identifiers
    CAS Number
    PubChem CID
    IUPHAR/BPS
    ChemSpider
    UNII
    KEGG
    ChEBI
    ECHA InfoCard 100.164.439 Edit this at Wikidata
    Chemical and physical data
    Formula C29H39NO9
    Molar mass 545.62 g/mol
    3D model (JSmol)

    Omacetaxine mepesuccinate (INN, trade names Synribo or Myelostat ), formerly named as homoharringtonine or HHT, is a pharmaceutical drug substance that is indicated for treatment of chronic myeloid leukemia (CML). It is a natural product first discovered in Cephalotaxus harringtonii, now manufactured by hemi-synthesis. It was approved by the US FDA in October 2012 for the treatment of adult patients with CML with resistance and/or intolerance to two or more tyrosine kinase inhibitors (TKIs).[1]

    Medical uses

    Omacetaxine/homoharringtonine is indicated for use as a treatment for patients with chronic myeloid leukaemia who are resistant or intolerant of tyrosine kinase inhibitors.[2][3][4]

    In June 2009, results of a long-term open label Phase II study were published, which investigated the use of omacetaxine infusions in CML patients. After twelve months of treatment, about one third of patients showed a cytogenetic response.[5] A study in patients who had failed imatinib and who had the drug resistant T315I mutation achieved cytogenetic response in 28% of patients and hematologic response in 80% of patients, according to preliminary data.[6]

    Phase I studies including a small number of patients have shown benefit in treating myelodysplastic syndrome (MDS, 25 patients)[7] and acute myelogenous leukaemia (AML, 76 patients).[8] Patients with solid tumors did not benefit from omacetaxine.[9]

    Adverse effects

    By frequency:[1][2]
    Very common (>10% frequency):

    • Diarrhoea
    • Myelosuppression†
    • Injection site reactions
    • Nausea
    • Fatigue
    • Fever
    • Muscle weakness
    • Joint pain
    • Headache
    • Cough
    • Hair loss
    • Constipation
    • Nosebleeds
    • Upper abdominal pain
    • Pain in the extremities
    • Oedema
    • Vomiting
    • Back pain
    • Hyperglycemia, sometimes extreme
    • Gout
    • Rash
    • Insomnia

    Common (1–10% frequency):

    • Seizures
    • Haemorrhage

    † Myelosuppression, including: thrombocytopenia, anaemia, neutropenia and lymphopenia, in descending order of frequency.

    Mechanism of action

    Omacetaxine is a protein translation inhibitor. It inhibits protein translation by preventing the initial elongation step of protein synthesis. It interacts with the ribosomal A-site and prevents the correct positioning of amino acid side chains of incoming aminoacyl-tRNAs. Omacetaxine acts only on the initial step of protein translation and does not inhibit protein synthesis from mRNAs that have already commenced translation.[10]

    References

    1. 1 2 "Synribo (omacetaxine) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Retrieved 18 February 2014.
    2. 1 2 "SYNRIBO (omacetaxine mepesuccinate) injection, powder, lyophilized, for solution [Cephalon, Inc.]". DailyMed. Cephalon, Inc. October 2012. Retrieved 18 February 2014.
    3. ↑ Sweetman, S, ed. (14 November 2012). "Omacetaxine Mepesuccinate". Martindale: The Complete Drug Reference. Medicines Complete. Pharmaceutical Press. |access-date= requires |url= (help)
    4. ↑ Lacroix, Marc (2014). Targeted Therapies in Cancer. Hauppauge , NY: Nova Sciences Publishers. ISBN 978-1-63321-687-7.
    5. ↑ Li, Y. F.; Deng, Z. K.; Xuan, H. B.; Zhu, J. B.; Ding, B. H.; Liu, X. N.; Chen, B. A. (2009). "Prolonged chronic phase in chronic myelogenous leukemia after homoharringtonine therapy". Chinese medical journal. 122 (12): 1413–1417. PMID 19567163.
    6. ↑ Quintás-Cardama, A.; Kantarjian, H.; Cortes, J. (2009). "Homoharringtonine, omacetaxine mepesuccinate, and chronic myeloid leukemia circa 2009". Cancer. 115 (23): 5382–5393. doi:10.1002/cncr.24601. PMID 19739234.
    7. ↑ Wu, L.; Li, X.; Su, J.; Chang, C.; He, Q.; Zhang, X.; Xu, L.; Song, L.; Pu, Q. (2009). "Effect of low-dose cytarabine, homoharringtonine and granulocyte colony-stimulating factor priming regimen on patients with advanced myelodysplastic syndrome or acute myeloid leukemia transformed from myelodysplastic syndrome". Leukemia & Lymphoma. 50 (9): 1461–7. doi:10.1080/10428190903096719. PMID 19672772.
    8. ↑ Gu, L. F.; Zhang, W. G.; Wang, F. X.; Cao, X. M.; Chen, Y. X.; He, A. L.; Liu, J.; Ma, X. R. (2010). "Low dose of homoharringtonine and cytarabine combined with granulocyte colony-stimulating factor priming on the outcome of relapsed or refractory acute myeloid leukemia". Journal of Cancer Research and Clinical Oncology. 137 (6): 997–1003. doi:10.1007/s00432-010-0947-z. PMID 21152934.
    9. ↑ Kantarjian, H. M.; Talpaz, M.; Santini, V.; Murgo, A.; Cheson, B.; O'Brien, S. M. (2001). "Homoharringtonine". Cancer. 92 (6): 1591–1605. doi:10.1002/1097-0142(20010915)92:6<1591::AID-CNCR1485>3.0.CO;2-U. PMID 11745238.
    10. ↑ Wetzler M, Segal D. Omacetaxine as an Anticancer Therapeutic: What is Old is New Again. Current Pharmaceutical Design 2011;17:59–64
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