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Panobinostat

Clinical data
Trade names	Farydak
Other names	LBH-589
AHFS/Drugs.com	Monograph
License data	US DailyMed: Panobinostat
Routes of administration	By mouth
ATC code	L01XH03 (WHO)
Legal status
Legal status	AU: S4 (Prescription only) US: ℞-only EU: Rx-only In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability	21%
Protein binding	90%
Metabolism	CYP3A (40%), CYP2D6, CYP2C19
Elimination half-life	37 hours
Excretion	Fecal (44–77%), renal (29–51%)
Identifiers
IUPAC name (2E)-N-hydroxy-3-amino}methyl)phenyl]acrylamide
CAS Number	404950-80-7
PubChem CID	6918837
IUPHAR/BPS	7489
DrugBank	DB06603
ChemSpider	5294028
UNII	9647FM7Y3Z
KEGG	D10319
ChEBI	CHEBI:85990
CompTox Dashboard (EPA)	DTXSID40193506
ECHA InfoCard	100.230.582
Chemical and physical data
Formula	C21H23N3O2
Molar mass	349.434 g·mol
3D model (JSmol)	Interactive image
SMILES O=C(NO)\C=C\c1ccc(cc1)CNCCc3c2ccccc2c3C
InChI InChI=1S/C21H23N3O2/c1-15-18(19-4-2-3-5-20(19)23-15)12-13-22-14-17-8-6-16(7-9-17)10-11-21(25)24-26/h2-11,22-23,26H,12-14H2,1H3,(H,24,25)/b11-10+ Key:FPOHNWQLNRZRFC-ZHACJKMWSA-N
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Panobinostat, sold under the brand name Farydak, is a medication used for the treatment of multiple myeloma. It is a hydroxamic acid and acts as a non-selective histone deacetylase inhibitor (pan-HDAC inhibitor).

Panobinostat was approved for medical use in the United States in February 2015, and in the European Union in August 2015. However, in March 2022, it was withdrawn in the United States.

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.

Contraindications

Panobinostat 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.

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.

Pharmacology

Mechanism of action

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

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.

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

Clinical trials

As of August 2012, it is being tested against Hodgkin's Lymphoma, cutaneous T cell lymphoma (CTCL) 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.

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.

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

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.

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

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.

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.

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.

Panobinostat was also identified as a senolytic, effective at killing senescent cells.

References

1. "Prescription medicines: registration of new chemical entities in Australia, 2016". Therapeutic Goods Administration (TGA). 21 June 2022. Retrieved 10 April 2023.
2. ^ "Farydak- panobinostat capsule". DailyMed. 27 July 2021. Retrieved 22 October 2022.
3. ^ "Farydak EPAR". European Medicines Agency. 17 September 2018. Retrieved 22 October 2022.
4. ^ 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.
5. Table 3: Select epigenetic inhibitors in various stages of development Archived 18 April 2016 at the Wayback Machine from Mack GS (December 2010). "To selectivity and beyond". Nature Biotechnology. 28 (12): 1259–66. doi:10.1038/nbt.1724. PMID 21139608. S2CID 11480326.
6. "Farydak Drug Approval Package". U.S. Food and Drug Administration (FDA). 17 March 2015. Retrieved 22 October 2022.
7. "Drug Trials Snapshot: Farydak (panobinostat)". U.S. Food and Drug Administration (FDA). 30 July 2020. Retrieved 22 October 2022.
8. "Farydak product details". European Medicines Agency. 17 September 2018. Archived from the original on 20 June 2018. Retrieved 1 February 2017.
9. "Withdrawn Oncology /Hematologic Malignancies Accelerated Approvals". U.S. Food and Drug Administration (FDA). 1 June 2022. Retrieved 22 October 2022.
10. "Secura Bio, Inc.; Withdrawal of Approval of New Drug Application for Farydak (panobinostat) Capsules, 10 Milligrams, 15 Milligrams, and 20 Milligrams". Federal Register. 24 March 2022. Retrieved 22 October 2022.
11. Rajkumar SV (2018). "Multiple Myeloma". In Hensley ML, Milowsky MI, Rajkumar SV, Schuetze SM (eds.). ASCO-SEP : Medical Oncology Self-Evaluation Program (7th ed.). Alexandria, VA: American Society of Clinical Oncology. ISBN 978-0-9983747-4-1. OCLC 1080368315.
12. ^ Haberfeld, H, ed. (2016). Austria-Codex (in German). Vienna: Österreichischer Apothekerverlag.
13. Clinical trial number NCT00425555 for "Study of Oral LBH589 in Adult Patients With Refractory Cutaneous T-Cell Lymphoma" at ClinicalTrials.gov
14. "Studies found for LBH-589". ClinicalTrials.gov.
15. Prince HM, Prince M (2009). "Panobinostat (LBH589): a novel pan-deacetylase inhibitor with activity in T cell lymphoma". Hematology Meeting Reports. 3 (1). Parkville, Australia: Peter MacCallum Cancer Centre and University of Melbourne: 33–38.
16. Simons J (27 April 2013). "Scientists on brink of HIV cure". The Telegraph. Archived from the original on 27 April 2013.
17. 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
18. Rasmussen TA, Tolstrup M, Brinkmann CR, Olesen R, Erikstrup C, Solomon A, et al. (October 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): e13-21. doi:10.1016/S2352-3018(14)70014-1. PMID 26423811.
19. Hoffman J (May 2016). "Panobinostat May Be Active in Select Patients With Refractory DLBCL". CancerTherapyAdvisor.com. Archived from the original on 8 August 2016. Retrieved 23 May 2016.
20. "Mayo Clinic Researchers Formulate Treatment Combination Lethal To Pancreatic Cancer Cells". The Mayo Clinic. Archived from the original on 20 February 2012.
21. Garbes L, Riessland M, Hölker I, Heller R, Hauke J, Tränkle C, et al. (October 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): 3645–58. doi:10.1093/hmg/ddp313. PMID 19584083.
22. Tate CR, Rhodes LV, Segar HC, Driver JL, Pounder FN, Burow ME, Collins-Burow BM (May 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.
23. Rasmussen TA, Schmeltz Søgaard O, Brinkmann C, Wightman F, Lewin SR, Melchjorsen J, et al. (May 2013). "Comparison of HDAC inhibitors in clinical development: effect on HIV production in latently infected cells and T-cell activation". Human Vaccines & Immunotherapeutics. 9 (5): 993–1001. doi:10.4161/hv.23800. PMC 3899169. PMID 23370291.
24. Grasso CS, Tang Y, Truffaux N, Berlow NE, Liu L, Debily MA, et al. (June 2015). "Functionally defined therapeutic targets in diffuse intrinsic pontine glioma". Nature Medicine. 21 (6): 555–9. doi:10.1038/nm.3855. PMC 4862411. PMID 25939062.
25. Samaraweera, L., Adomako, A., Rodriguez-Gabin, A. et al. A Novel Indication for Panobinostat as a Senolytic Drug in NSCLC and HNSCC. Sci Rep 7, 1900 (2017). https://doi.org/10.1038/s41598-017-01964-1/PMID: 28507307 PMCID: PMC5432488

• Medicine

• CYP2D6 inhibitors
• Tryptamines
• Hydroxamic acids
• Histone deacetylase inhibitors
• Drugs developed by Novartis
• Cancer treatments
• Orphan drugs