Panobinostat

Absorption

After a 20 mg dose, panobinostat was quickly absorbed with a time to maximum absorption of 2 hours.

Toxicity

Farydak carries a Boxed Warning alerting patients and health care professionals that severe diarrhea and severe and fatal cardiac events, arrhythmias and electrocardiogram (ECG) changes have occurred in patients receiving Farydak. Because of these risks, Farydak is being approved with a Risk Evaluation and Mitigation Strategy (REMS) consisting of a communication plan to inform health care professionals of these risks and how to minimize them.

Description

Panobinostat is a potent inhibitor of all histone deacetylases (HDACs), with K_i values ranging from 0.6 to 31 nM for HDAC1-11. Through this action, it leads to acetylation of a range of cellular proteins, resulting in cell cycle arrest and apoptosis in cancer cells. It has potential applications in several different forms of cancer as well as in spinal muscular atrophy and HIV therapy.

Chemical properties

Yellow Solid

The Uses of Panobinostat

The novel labelled histone deacetylase inhibitor, LBH589, induces expression of DNA damage response genes and apoptosis in Ph- acute lymphoblastic leukemia cells.

The Uses of Panobinostat

The novel histone deacetylase inhibitor, LBH589, induces expression of DNA damage response genes and apoptosis in Ph- acute lymphoblastic leukemia cells.

Background

Panobinostat is an oral deacetylace (DAC) inhibitor approved on February 23, 2015 by the FDA for the treatment of multiple myeloma. The approval was accelerated based on progression-free survival, therefore confirmatory trials by the sponsor to demonstrate clinical efficacy in multiple myeloma treatment are in progress of being conducted. Panobinostat is marketed by Novartis under the brand name Farydak. Panobinostat acts as a non-selective histone deacetylase inhibitor (pan-HDAC inhibitor) and it is the most potent DAC inhibiting agent available on the market.

What are the applications of Application

Panobinostat is a histone deacetylase (HDAC) inhibitor reported to inhibit human multiple myeloma cell lines.

Indications

Panobinostat is indicated in the treatment of multiple myeloma in combination with dexamethasone and bortezomib in patients who have received 2 previous treatment regimens including bortezomib and an immunomodulatory agent. This indication is approved by accelerated approval based on progression free survival as of February 23, 2015.

Definition

ChEBI: A hydroxamic acid obtained by formal condensation of the carboxy group of (2E)-3-[4-({[2-(2-methylindol-3-yl)ethyl]amino}methyl)phenyl]prop-2-enoic acid with the amino group of hydroxylamine. A histone deacetylase inhibitor used (as its la tate salt) in combination with bortezomib and dexamethasone for the treatment of multiple myeloma.

Clinical Use

Histone deacetylase (HDAC) inhibitor:
Treatment of relapsed and/or refractory multiple myeloma

Drug interactions

Potentially hazardous interactions with other drugs
Analgesics: avoid with dextromethorphan possibly increased risk of ventricular arrhythmias with methadone - avoid.
Anti-arrhythmics: increased risk of ventricular arrhythmias with amiodarone and possibly disopyramide - avoid.
Antibacterials: increased risk of ventricular arrhythmias with clarithromycin and moxifloxacin - avoid; avoid with rifampicin.
Antidepressants: avoid with St John’s wort.
Antiepileptics: avoid with carbamazepine, fosphenytoin, phenobarbital, phenytoin and primidone.
Antifungals: concentration increased by ketoconazole and possibly posaconazole and voriconazole - reduce panobinostat dose; concentration possibly increased by itraconazole - avoid.
Antimalarials: possibly increased risk of ventricular arrhythmias with chloroquine - avoid.
Antipsychotics: avoid with pimozide.
Antivirals: concentration possibly increased by ritonavir and saquinavir - reduce dose of panobinostat.
Beta-blockers: possibly increased risk of ventricular arrhythmias with sotalol - avoid.
Grapefruit juice: avoid concomitant use.
5HT3 antagonists: possibly increased risk of ventricular arrhythmias with granisetron and ondansetron - avoid with granisetron.

Metabolism

Panobinostat is extensively metabolised, and a large fraction of the dose is metabolised before reaching the systemic circulation by reduction, hydrolysis, oxidation and glucuronidation. Oxidative metabolism of panobinostat played a less prominent role, with approximately 40% of the dose eliminated by this pathway. Cytochrome P450 3A4 (CYP3A4) is the main oxidation enzyme, with potential minor involvement of CYP2D6 and 2C19.
Panobinostat represented 6-9% of the drug-related exposure in plasma. The parent substance is deemed to be responsible for the overall pharmacological activity of panobinostat.
After a single oral dose of [14C]-panobinostat in patients, 29-51% of administered radioactivity is excreted in the urine and 44-77% in the faeces. Unchanged panobinostat accounted for <2.5% of the dose in urine and <3.5% of the dose in faeces.

Metabolism

Panobinostat was extensively metabolized to 77 metabolites. Unchanged panobinostat recovered in urine and feces was 2% and 3%, respectively. Primary metabolic pathways of panobinostat are reduction, hydrolysis, oxidation, and glucuronidation processes. CYP and non-CYP enzymes were found to play significant role in metabolism, CYP2D6 and CYP2C19 playing minor roles.

storage

Store at -20°C

References

1) Geng et al. (2006), Histone deacetylase (HDAC) inhibitor LBH589 increases duration of gamma H2AX foci and confines HDAC4 to the cytoplasm in irradiated non-small cell lung cancer; Cancer Res., 66 11298 2) George et al. (2005), Combination of the histone deacetylase inhibitor LBH589 and the hsp90 inhibitor 17-AAG is highly active against human CML-BC cells and AML cells with activating mutation of FLT-3; Blood, 105 1768 3) Maiso et al. (2006), The histone deacetylase inhibitor LBH589 is a potent antimyeloma agent that overcomes drug resistance; Cancer Res., 66 5781