Vorinostat

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Vorinostat
Vorinostat.svg
Names
PronunciationVorinostat /vɒˈrɪnstæt/ vorr-IN-oh-stat
Zolinza (/zˈlɪnzə/ zoh-LIN-zə
Trade namesZolinza, Vorinostat MSD, others
Other namesSuberanilohydroxamic acid (SAHA)
  • 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]
Pregnancy
category
  • US: D (Evidence of risk)
Routes of
use
By mouth (capsules)
Typical dose400 mg OD[1]
External links
AHFS/Drugs.comMonograph
US NLMVorinostat
MedlinePlusa607050
Legal
License data
Legal status
  • US: ℞-only
  • In general: ℞ (Prescription only)
Pharmacokinetics
Bioavailability1.8–11%[2]
Protein binding~71%
MetabolismHepatic 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)
ExcretionRenal (negligible)
Chemical and physical data
FormulaC14H20N2O3
Molar mass264.325 g·mol−1
3D model (JSmol)
  • O=C(Nc1ccccc1)CCCCCCC(=O)NO
  • 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
 ☒NcheckY (what is this?)  (verify)

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in 2006.[1] While it was given orphan medication status in Europe in 2004, in 2009 the application for approval was withdrawn.[4] In the United States it costs about 14,600 USD per month as of 2021.[5]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

References

  1. 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 1.12 "Vorinostat Monograph for Professionals". Drugs.com. 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. Retrieved 1 September 2016.
  3. "Zolinza (vorinostat) Capsules. Full Prescribing Information" (PDF). Merck & Co., Inc., Whitehouse Station, NJ 08889, USA. Retrieved 1 September 2016.
  4. 4.0 4.1 "Vorinostat MSD: Withdrawal of the marketing authorisation application". Retrieved 16 September 2021.
  5. "Zolinza Prices, Coupons & Savings Tips - GoodRx". GoodRx. Retrieved 16 September 2021.
  6. 6.0 6.1 "Zolinza (vorinostat) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Retrieved 16 February 2014.
  7. 7.0 7.1 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.
  10. HDAC Inhibitors Base (vorinostat)
  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". Retrieved 2008-02-15.
  13. "Vorinostat shows anti-cancer activity in recurrent gliomas" (Press release). Mayo Clinic. June 3, 2007. 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)".

External links

Identifiers: