Vorinostat

Vorinostat
Names
PronunciationVorinostat /vɒˈrɪnstæt/ vorr-IN-oh-stat
Zolinza (/zˈlɪnzə/ zoh-LIN-zə
Trade namesZolinza, Vorinostat MSD, others
Other namesSuberanilohydroxamic acid (SAHA)
IUPAC name
  • N-Hydroxy-N'-phenyloctanediamide
Clinical data
Drug classHistone deacetylase inhibitors (HDI)[1]
Main usesCutaneous T cell lymphoma (CTCL)[1]
Side effectsDiarrhea, tiredness, change in taste, low platelets, hair loss, cough, fever[1]
WHO AWaReUnlinkedWikibase error: ⧼unlinkedwikibase-error-statements-entity-not-set⧽
Pregnancy
category
  • US: D (Evidence of risk)
    Routes of
    use
    By mouth (capsules)
    Typical dose400 mg OD[1]
    External links
    AHFS/Drugs.comMonograph
    MedlinePlusa607050
    Legal
    License data
    Legal status
    • US: ℞-only
    • In general: ℞ (Prescription only)
    Pharmacokinetics
    Bioavailability1.8–11%[2]
    Protein binding~71%
    MetabolismLiver glucuronidation and β-oxidation
    CYP system not involved
    Metabolitesvorinostat O-glucuronide, 4-anilino-4-oxobutanoic acid (both inactive)[3]
    Elimination half-life~2 hours (vorinostat and O-glucuronide), 11 hours (4-anilino-4-oxobutanoic acid)
    ExcretionKidney (negligible)
    Chemical and physical data
    FormulaC14H20N2O3
    Molar mass264.325 g·mol−1
    3D model (JSmol)
    SMILES
    • O=C(Nc1ccccc1)CCCCCCC(=O)NO
    InChI
    • InChI=1S/C14H20N2O3/c17-13(15-12-8-4-3-5-9-12)10-6-1-2-7-11-14(18)16-19/h3-5,8-9,19H,1-2,6-7,10-11H2,(H,15,17)(H,16,18) checkY
    • Key:WAEXFXRVDQXREF-UHFFFAOYSA-N checkY

    Vorinostat, sold under the brand name Zolinza, is a medication used for cutaneous T cell lymphoma (CTCL).[1] Specifically it is used when the disease persists, gets worse, or comes back during or after two other treatments.[1] It is taken by mouth.[1]

    Common side effects include diarrhea, tiredness, change in taste, low platelets, hair loss, cough, and fever.[1] Other severe side effects may include blood clots and high blood sugar.[1] Use during pregnancy may harm the baby.[1] It is a histone deacetylase inhibitors (HDI).[1]

    Vorinostat was approved for medical use in the United States in 2006.[1] While it was given orphan medication status in Europe in 2004, in 2009 the application for approval was withdrawn.[4] In the United States it costs about 14,600 USD per month as of 2021.[5]

    Medical uses

    Vorinostat is used for CTCL.[6] The European Medicines Agency in 2009 viewed the benefit as being unclear and thus it was not approved for use their.[4]

    Dosage

    The typical dose is 400 mg taken once per day.[1]

    Mechanism of action

    Vorinostat has been shown to bind to the active site of histone deacetylases and act as a chelator for zinc ions also found in the active site of histone deacetylases.[7] Vorinostat's inhibition of histone deacetylases results in the accumulation of acetylated histones and acetylated proteins, including transcription factors crucial for the expression of genes needed to induce cell differentiation.[7] It acts on class I, II and IV of histone deacetylase.

    History

    The compound was developed by Columbia University chemist Ronald Breslow and Memorial Sloan-Kettering researcher Paul Marks.[8][9]

    Vorinostat was the first histone deacetylase inhibitor[10] approved by the U.S. Food and Drug Administration (FDA) for the treatment of CTCL on October 6, 2006.[6]

    Research

    It failed to demonstrate efficacy in treating acute myeloid leukemia in a phase II study.[11]

    Vorinostat has also been used to treat Sézary syndrome, another type of lymphoma closely related to CTCL.[12]

    A study suggested that vorinostat also possesses some activity against recurrent glioblastoma multiforme, resulting in a median overall survival of 5.7 months (compared to 4–4.4 months in earlier studies).[13] Further brain tumor trials are planned in which vorinostat will be combined with other drugs.

    Including vorinostat in treatment of advanced non-small-cell lung carcinoma (NSCLC) showed improved response rates and increased median progression free survival and overall survival.[14]

    It has given encouraging results in a phase II trial for myelodysplastic syndromes in combination with idarubicin and cytarabine.[15]

    See also

    • Trichostatin A

    References

    1. 1 2 3 4 5 6 7 8 9 10 11 12 13 "Vorinostat Monograph for Professionals". Drugs.com. Archived from the original on 4 March 2016. Retrieved 16 September 2021.
    2. "Withdrawal Assessment Report for Vorinostat MSD 100 mg Hard Capsules (vorinostat)" (PDF). European Medicines Agency. 23 October 2008. p. 9. Archived (PDF) from the original on 15 September 2016. Retrieved 1 September 2016.
    3. "Zolinza (vorinostat) Capsules. Full Prescribing Information" (PDF). Merck & Co., Inc., Whitehouse Station, NJ 08889, USA. Archived (PDF) from the original on 2 October 2016. Retrieved 1 September 2016.
    4. 1 2 "Vorinostat MSD: Withdrawal of the marketing authorisation application". Archived from the original on 22 September 2021. Retrieved 16 September 2021.
    5. "Zolinza Prices, Coupons & Savings Tips - GoodRx". GoodRx. Archived from the original on 14 June 2016. Retrieved 16 September 2021.
    6. 1 2 "Zolinza (vorinostat) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Archived from the original on 21 February 2014. Retrieved 16 February 2014.
    7. 1 2 Marks PA, Dokmanovic M (December 2005). "Histone deacetylase inhibitors: discovery and development as anticancer agents". Expert Opinion on Investigational Drugs. 14 (12): 1497–511. doi:10.1038/sj.bjc.6603463. PMC 2360770. PMID 16307490.
    8. Lee JH, Mahendran A, Yao Y, Ngo L, Venta-Perez G, Choy ML, et al. (September 2013). "Development of a histone deacetylase 6 inhibitor and its biological effects". Proceedings of the National Academy of Sciences of the United States of America. 110 (39): 15704–9. Bibcode:2013PNAS..11015704L. doi:10.1073/pnas.1313893110. PMC 3785767. PMID 24023063.
    9. Marks PA, Breslow R (January 2007). "Dimethyl sulfoxide to vorinostat: development of this histone deacetylase inhibitor as an anticancer drug". Nature Biotechnology. 25 (1): 84–90. doi:10.1038/nbt1272. PMID 17211407. Archived from the original on 2021-08-27. Retrieved 2021-07-12.
    10. "HDAC Inhibitors Base (vorinostat)". Archived from the original on 2020-07-12. Retrieved 2021-07-12.
    11. Schaefer EW, Loaiza-Bonilla A, Juckett M, DiPersio JF, Roy V, Slack J, et al. (October 2009). "A phase 2 study of vorinostat in acute myeloid leukemia". Haematologica. 94 (10): 1375–82. doi:10.3324/haematol.2009.009217. PMC 2754953. PMID 19794082.
    12. Cuneo A C. "Mycosis fungoides/Sezary's syndrome". Archived from the original on 2008-02-12. Retrieved 2008-02-15.
    13. "Vorinostat shows anti-cancer activity in recurrent gliomas" (Press release). Mayo Clinic. June 3, 2007. Archived from the original on 2007-10-10. Retrieved 2007-06-03.
    14. Ramalingam SS, Maitland ML, Frankel P, Argiris AE, Koczywas M, Gitlitz B, et al. (January 2010). "Carboplatin and Paclitaxel in combination with either vorinostat or placebo for first-line therapy of advanced non-small-cell lung cancer". Journal of Clinical Oncology. 28 (1): 56–62. doi:10.1200/JCO.2009.24.9094. PMC 2799233. PMID 19933908.
    15. "Zolinza, Idarubicin, Cytarabine Combination Yields High Response Rates In MDS Patients (ASH 2011)". Archived from the original on 2014-10-30. Retrieved 2021-07-12.
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