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Omacetaxine mepesuccinate

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Omacetaxine mepesuccinate
Clinical data
Trade namesSynribo
AHFS/Drugs.comMonograph
License data
Routes of
administration		Subcutaneous, intravenous infusion
ATC code
Legal status
Legal status
Pharmacokinetic data
Protein binding50%
MetabolismMostly via plasma esterases
Elimination half-life6 hours
ExcretionUrine (≤15% unchanged)
Identifiers
  • 1-((1S,3aR,14bS)-2-Methoxy-1,5,6,8,9,14b-hexahydro-4H-cyclopenta(a)(1,3)dioxolo(4,5-h)pyrrolo(2,1-b)(3)benzazepin-1-yl) 4-methyl (2R)-2-hydroxy-2-(4-hydroxy-4-methylpentyl)butanedioate
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
UNII
KEGG
ChEBI
CompTox Dashboard (EPA)
ECHA InfoCard100.164.439 Edit this at Wikidata
Chemical and physical data
FormulaC29H39NO9
Molar mass545.62 g/mol g·mol−1
3D model (JSmol)
  • CC(C)(CCC[C@@](CC(=O)OC)(C(=O)O[C@H]1[C@H]2c3cc4c(cc3CCN5[C@@]2(CCC5)C=C1OC)OCO4)O)O
  • InChI=1S/C29H39NO9/c1-27(2,33)8-5-10-29(34,16-23(31)36-4)26(32)39-25-22(35-3)15-28-9-6-11-30(28)12-7-18-13-20-21(38-17-37-20)14-19(18)24(25)28/h13-15,24-25,33-34H,5-12,16-17H2,1-4H3/t24-,25-,28+,29-/m1/s1
  • Key:HYFHYPWGAURHIV-JFIAXGOJSA-N

Omacetaxine mepesuccinate (INN, trade names Synribo ), 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. ^ a b "Synribo (omacetaxine) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Retrieved 18 February 2014.
  2. ^ a b "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. Pharmaceutical Press. {{cite book}}: |access-date= requires |url= (help); |work= ignored (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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