Panobinostat

Panobinostat (trade name Farydak /ˈfɛərədæk/ FAIR-ə-dak) is a drug by Novartis for the treatment of various cancers. It is a hydroxamic acid[2] and acts as a non-selective histone deacetylase inhibitor (pan-HDAC inhibitor).[3]

Panobinostat
Clinical data
Trade namesFarydak
Other namesLBH-589
AHFS/Drugs.comfarydak
License data
Routes of
administration		By mouth (capsules)
ATC code
Legal status
Legal status
  • US: ℞-only
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability21%[1]
Protein binding90%[1]
MetabolismCYP3A (40%), CYP2D6, CYP2C19[1]
Elimination half-life37 hours[1]
ExcretionFecal (44–77%), renal (29–51%)[1]
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
CompTox Dashboard (EPA)
ECHA InfoCard100.230.582
Chemical and physical data
FormulaC21H23N3O2
Molar mass349.42622 g/mol g·mol−1
3D model (JSmol)
 NY (what is this?)  (verify)

On 23 February 2015 it received FDA accelerated approval for use in patients with multiple myeloma,[4][5] and on 28 August 2015 it was approved by the European Medicines Agency for the same use.[6]

Medical uses

Panobinostat is used in combination with the anti-cancer drug bortezomib and the corticoid dexamethasone for the treatment of multiple myeloma in adults who had received at least two previous treatments, including bortezomib and an immunomodulatory agent.[4][7]

Contraindications

The drug is contraindicated in nursing mothers. To judge from experiments in animals, there is a risk for the unborn child if used during pregnancy; still, the benefit of panobinostat may outweigh this risk.[7]

Side effects

Common side effects (in more than 10% of patients) include low blood cell counts (pancytopenia, thrombocytopenia, anaemia, leucopenia, neutropenia, lymphopenia), airway infections, as well as unspecific reactions such as fatigue, diarrhoea, nausea, headache, and sleeping problems.[7]

Pharmacology

Mechanism of action

Panobinostat inhibits multiple histone deacetylase enzymes, a mechanism leading to apoptosis of malignant cells via multiple pathways.[2]

Pharmacokinetics

Panobinostat is absorbed quickly and almost completely from the gut, but has a significant first-pass effect, resulting in a total bioavailability of 21%. Highest blood plasma levels in patients with advanced cancer are reached after two hours. Plasma protein binding is about 90%. The substance is metabolised mainly through oxidation by the liver enzyme CYP3A4 and to a small extent by CYP2D6 and CYP2C19. It is also reduced, hydrolyzed and glucuronidized by unspecified enzymes. All metabolites seem to be inactive.[7]

Biological half-life is estimated to be 37 hours. 29–51% are excreted via the urine and 44–77% via the faeces.[7]

Studies

Clinical trials

As of August 2012, it is being tested against Hodgkin's Lymphoma, cutaneous T cell lymphoma (CTCL)[8] and other types of malignant disease in Phase III clinical trials, against myelodysplastic syndromes, breast cancer and prostate cancer in Phase II trials, and against chronic myelomonocytic leukemia (CMML) in a Phase I trial.[9][10]

As of 2014 panobinostat is being used in a Phase I/II clinical trial that aims at curing AIDS in patients on highly active antiretroviral therapy (HAART). In this technique, panobinostat is used to drive the HIV DNA out of the patient's DNA, in the expectation that the patient's immune system in combination with HAART will destroy it.[11][12][13]

As of 2016 panobinostat is being studied in a phase II trial for relapsed and refractory diffuse large B-cell lymphoma (DLBCL).[14]

Preclinical studies

Panobinostat has been found to synergistically act with sirolimus to kill pancreatic cancer cells in the laboratory in a Mayo Clinic study. In the study, investigators found that this combination destroyed up to 65 percent of cultured pancreatic tumor cells. The finding is significant because the three cell lines studied were all resistant to the effects of chemotherapy – as are many pancreatic tumors.[15]

Panobinostat has also been found to significantly increase in vitro the survival of motor neuron (SMN) protein levels in cells of patients suffering from spinal muscular atrophy.[16]

Panobinostat was able to selectively target triple negative breast cancer (TNBC) cells by inducing hyperacetylation and cell cycle arrest at the G2-M DNA damage checkpoint; partially reversing the morphological changes characteristic of breast cancer cells.[17]

Panobinostat, along with other HDAC inhibitors, is also being studied for potential to induce virus HIV-1 expression in latently infected cells and disrupt latency. These resting cells are not recognized by the immune system as harboring the virus and do not respond to antiretroviral drugs.[18]

A 2015 study suggested Panobinostat was effective in preventing diffuse intrinsic pontine glioma cell growth in vitro and in vivo, identifying it as a potential drug candidate.[19]

References
  1. Panobinostat Package Insert
  2. Revill, P; Mealy, N; Serradell, N; Bolos, J; Rosa, E (2007). "Panobinostat". Drugs of the Future. 32 (4): 315. doi:10.1358/dof.2007.032.04.1094476. ISSN 0377-8282.
  3. Table 3: Select epigenetic inhibitors in various stages of development from Mack, G. S. (2010). "To selectivity and beyond". Nature Biotechnology. 28 (12): 1259–1266. doi:10.1038/nbt.1724. PMID 21139608.
  4. FDA.gov announcement about accelerated approval of panobinostat (Farydak)
  5. Panobinostat chemotherapy regimen for multiple myeloma (MM wiki)
  6. "Farydak product details". European Medicines Agency.
  7. Haberfeld, H, ed. (2016). Austria-Codex (in German). Vienna: Österreichischer Apothekerverlag.
  8. Clinical trial number NCT00425555 for "Study of Oral LBH589 in Adult Patients With Refractory Cutaneous T-Cell Lymphoma" at ClinicalTrials.gov
  9. ClinicalTrials.gov: LBH-589
  10. Prince, HM; M Bishton (2009). "Panobinostat (LBH589): a novel pan-deacetylase inhibitor with activity in T cell lymphoma". Hematology Meeting Reports. Parkville, Australia: Peter MacCallum Cancer Centre and University of Melbourne. 3 (1): 33–38.
  11. Simons, J (27 April 2013). "Scientists on brink of HIV cure". The Telegraph.
  12. Clinical trial number NCT01680094 for "Safety and Effect of The HDAC Inhibitor Panobinostat on HIV-1 Expression in Patients on Suppressive HAART (CLEAR)" at ClinicalTrials.gov
  13. Rasmussen, T. A.; Tolstrup, M.; Brinkmann, C. R.; Olesen, R.; Erikstrup, C.; Solomon, A.; Winckelmann, A.; Palmer, S.; Dinarello, C.; Buzon, M.; Lichterfeld, M.; Lewin, S. R.; Østergaard, L.; Søgaard, O. S. (2014). "Panobinostat, a histone deacetylase inhibitor, for latent-virus reactivation in HIV-infected patients on suppressive antiretroviral therapy: A phase 1/2, single group, clinical trial". The Lancet HIV. 1 (1): e13–e21. doi:10.1016/S2352-3018(14)70014-1. PMID 26423811.
  14. Panobinostat May Be Active in Select Patients With Refractory DLBCL. May 2016
  15. Mayo Clinic Researchers Formulate Treatment Combination Lethal To Pancreatic Cancer Cells
  16. Garbes, L; Riessland, M; Hölker, I; Heller, R; Hauke, J; Tränkle, Ch; Coras, R; Blümcke, I; Hahnen, E; Wirth, B (2009). "LBH589 induces up to 10-fold SMN protein levels by several independent mechanisms and is effective even in cells from SMA patients non-responsive to valproate". Human Molecular Genetics. 18 (19): 3645–3658. doi:10.1093/hmg/ddp313. PMID 19584083. Archived from the original on 2012-07-11.
  17. Tate, CR; Rhodes, LV; Segar, HC; Driver, JL; Pounder, FN; Burow, ME; Collins-Burow, BM (2012). "Targeting triple-negative breast cancer cells with the histone deacetylase inhibitor panobinostat". Breast Cancer Research. 14 (3): R79. doi:10.1186/bcr3192. PMC 3446342. PMID 22613095.
  18. TA Rasmussen, et al. Comparison of HDAC inhibitors in clinical development: Effect on HIV production in latently infected cells and T-cell activation. Human Vaccines & Immunotherapeutics 9:5, 1–9, May 2013.
  19. Grasso, Catherine (4 May 2015). "Functionally defined therapeutic targets in diffuse intrinsic pontine glioma". Nature Medicine. 21 (6): 555–559. doi:10.1038/nm.3855. PMC 4862411. PMID 25939062.


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