Panobinostat

Identification

Summary

Panobinostat is a non-selective histone deacetylase inhibitor used to treat multiple myeloma in combination with other antineoplastic agents.

Brand Names
Farydak
Generic Name
Panobinostat
DrugBank Accession Number
DB06603
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.

Type
Small Molecule
Groups
Approved, Investigational
Structure
Weight
Average: 349.434
Monoisotopic: 349.179026993
Chemical Formula
C21H23N3O2
Synonyms
  • (2E)-N-hydroxy-3-[4-({[2-(2-methyl-1H-indol-3-yl)ethyl]amino}methyl)phenyl]acrylamide
  • 2-PROPENAMIDE, N-HYDROXY-3-(4-(((2-(2-METHYL-1H-INDOL-3-YL)ETHYL)AMINO)METHYL)PHENYL)-, (2E)-
  • hydroxypropyl-B-cyclodextrin-panobinostat complex
  • Panobinostat
  • Panobinostatum

Pharmacology

Indication

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.

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Used in combination to treatRefractory multiple myelomaRegimen in combination with: Dexamethasone (DB01234), Bortezomib (DB00188)••••••••••••
Contraindications & Blackbox Warnings
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Pharmacodynamics

Not Available

Mechanism of action

Panobinostat is a deacetylase (DAC) inhibitor. DACs, also known as histone DACs (HDAC), are responsible for regulating the acetylation of about 1750 proteins in the body; their functions are involved in many biological processes including DNA replication and repair, chromatin remodelling, transcription of genes, progression of the cell-cycle, protein degradation and cytoskeletal reorganization. In multiple myeloma, there is an overexpression of DAC proteins. Panobinostat inhibits class I (HDACs 1, 2, 3, 8), class II (HDACs 4, 5, 6, 7, 9, 10) and class IV (HDAC 11) proteins. Panobinostat's antitumor activity is believed to be attributed to epigenetic modulation of gene expression and inhibition of protein metabolism. Panobinostat also exhibits cytotoxic synergy with bortezomib, a proteasome inhibitor concurrently used in treatment of multiple myeloma.

TargetActionsOrganism
AHistone deacetylase
inhibitor
Humans
Absorption

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

Volume of distribution

Not Available

Protein binding

Not Available

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.

Route of elimination

Not Available

Half-life

30 hours

Clearance

Not Available

Adverse Effects
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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.

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AbametapirThe serum concentration of Panobinostat can be increased when it is combined with Abametapir.
AbataceptThe metabolism of Panobinostat can be increased when combined with Abatacept.
AbemaciclibThe serum concentration of Abemaciclib can be increased when it is combined with Panobinostat.
AbrocitinibThe serum concentration of Panobinostat can be increased when it is combined with Abrocitinib.
AcalabrutinibThe metabolism of Panobinostat can be decreased when combined with Acalabrutinib.
Food Interactions
  • Avoid grapefruit products. Grapefruit inhibits CYP3A4 metabolism, which may increase the serum concentration of panobinostat.
  • Exercise caution with St. John's Wort. This herb induces CYP3A4 metabolism, which may reduce the serum concentration of panobinostat.
  • Take at the same time every day.
  • Take with a full glass of water.
  • Take with or without food.

Products

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Product Ingredients
IngredientUNIICASInChI Key
Panobinostat hydrateD07V79Q44TNot AvailableYUKVPQZUSANPNW-ASTDGNLGSA-N
Panobinostat lactateHN0T99OO4V960055-56-5XVDWNSFFSMWXJJ-ASTDGNLGSA-N
International/Other Brands
Faridak / Farydak
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
FarydakCapsule10 mgOralZr Pharma& Gmb H2016-09-08Not applicableEU flag
FarydakCapsule20 mgOralZr Pharma& Gmb H2016-09-08Not applicableEU flag
FarydakCapsule10 mg/1OralNovartis Pharmaceuticals Corporation2015-02-232023-01-31US flag
FarydakCapsule15 mgOralZr Pharma& Gmb H2016-09-08Not applicableEU flag
FarydakCapsule10 mg/1OralSecura Bio, Inc.2015-02-23Not applicableUS flag

Categories

ATC Codes
L01XH03 — Panobinostat
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as tryptamines and derivatives. These are compounds containing the tryptamine backbone, which is structurally characterized by an indole ring substituted at the 3-position by an ethanamine.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Indoles and derivatives
Sub Class
Tryptamines and derivatives
Direct Parent
Tryptamines and derivatives
Alternative Parents
Cinnamic acids and derivatives / 3-alkylindoles / Styrenes / Phenylmethylamines / Benzylamines / Aralkylamines / Substituted pyrroles / Heteroaromatic compounds / Hydroxamic acids / Amino acids and derivatives
show 6 more
Substituents
3-alkylindole / Amine / Amino acid or derivatives / Aralkylamine / Aromatic heteropolycyclic compound / Azacycle / Benzenoid / Benzylamine / Carbonyl group / Carboxylic acid derivative
show 19 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
secondary amino compound, hydroxamic acid, cinnamamides, methylindole (CHEBI:85990)
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
9647FM7Y3Z
CAS number
404950-80-7
InChI Key
FPOHNWQLNRZRFC-ZHACJKMWSA-N
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+
IUPAC Name
(2E)-N-hydroxy-3-[4-({[2-(2-methyl-1H-indol-3-yl)ethyl]amino}methyl)phenyl]prop-2-enamide
SMILES
CC1=C(CCNCC2=CC=C(\C=C\C(=O)NO)C=C2)C2=CC=CC=C2N1

References

General References
  1. Qian DZ, Kato Y, Shabbeer S, Wei Y, Verheul HM, Salumbides B, Sanni T, Atadja P, Pili R: Targeting tumor angiogenesis with histone deacetylase inhibitors: the hydroxamic acid derivative LBH589. Clin Cancer Res. 2006 Jan 15;12(2):634-42. [Article]
  2. Laubach JP, Moreau P, San-Miguel JF, Richardson PG: Panobinostat for the Treatment of Multiple Myeloma. Clin Cancer Res. 2015 Nov 1;21(21):4767-73. doi: 10.1158/1078-0432.CCR-15-0530. Epub 2015 Sep 11. [Article]
  3. Link [Link]
  4. Drugs of the Future - Panobinostat [Link]
KEGG Drug
D10019
PubChem Compound
6918837
PubChem Substance
310264874
ChemSpider
5294028
BindingDB
29589
RxNav
1603350
ChEBI
85990
ChEMBL
CHEMBL483254
ZINC
ZINC000022010649
PharmGKB
PA166161307
PDBe Ligand
LBH
Drugs.com
Drugs.com Drug Page
Wikipedia
Panobinostat
PDB Entries
5ef8
FDA label
Download (772 KB)
MSDS
Download (227 KB)

Clinical Trials

Clinical Trials

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
CapsuleOral10 mg/1
CapsuleOral15 mg/1
CapsuleOral20 mg/1
CapsuleOral10 mg
CapsuleOral15 mg
CapsuleOral20 mg
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US7067551No2006-06-272021-08-31US flag
US6833384No2004-12-212021-09-30US flag
US8883842No2014-11-112028-06-13US flag
US6552065No2003-04-222021-08-31US flag
US7989494No2011-08-022028-01-17US flag

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.00198 mg/mLALOGPS
logP3.16ALOGPS
logP2.48Chemaxon
logS-5.2ALOGPS
pKa (Strongest Acidic)9.31Chemaxon
pKa (Strongest Basic)9.95Chemaxon
Physiological Charge1Chemaxon
Hydrogen Acceptor Count3Chemaxon
Hydrogen Donor Count4Chemaxon
Polar Surface Area77.15 Å2Chemaxon
Rotatable Bond Count7Chemaxon
Refractivity105.5 m3·mol-1Chemaxon
Polarizability38.94 Å3Chemaxon
Number of Rings3Chemaxon
Bioavailability1Chemaxon
Rule of FiveYesChemaxon
Ghose FilterYesChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleYesChemaxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSsplash10-0gb9-0009000000-95f7252268acfe0fbab2
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-014i-1009000000-93ff24717c5d00ea59ad
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-0ldj-0679000000-cb50a9738303fc1e8fac
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-00r6-9324000000-b98c8fcafc9fa806aebe
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-0a4i-4941000000-44f4841f32e10976edc6
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-001l-0901000000-3d4fdd55d793f00a9c97
Predicted 1H NMR Spectrum1D NMRNot Applicable
Predicted 13C NMR Spectrum1D NMRNot Applicable
Chromatographic Properties
Collision Cross Sections (CCS)
AdductCCS Value (Å2)Source typeSource
[M-H]-207.7104289
predicted
DarkChem Lite v0.1.0
[M-H]-185.19916
predicted
DeepCCS 1.0 (2019)
[M+H]+207.9414289
predicted
DarkChem Lite v0.1.0
[M+H]+187.55716
predicted
DeepCCS 1.0 (2019)
[M+Na]+208.0041289
predicted
DarkChem Lite v0.1.0
[M+Na]+194.2824
predicted
DeepCCS 1.0 (2019)

Targets

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insights and accelerate drug research.
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Kind
Protein group
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Transcription regulatory region sequence-specific dna binding
Specific Function
Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4). Histone deacetylation gives a tag for epigenetic repression and plays an impo...

Components:
References
  1. Beckers T, Burkhardt C, Wieland H, Gimmnich P, Ciossek T, Maier T, Sanders K: Distinct pharmacological properties of second generation HDAC inhibitors with the benzamide or hydroxamate head group. Int J Cancer. 2007 Sep 1;121(5):1138-48. [Article]
  2. Geng L, Cuneo KC, Fu A, Tu T, Atadja PW, Hallahan DE: 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. 2006 Dec 1;66(23):11298-304. [Article]
  3. Favreau AJ, McGlauflin RE, Duarte CW, Sathyanarayana P: miR-199b, a novel tumor suppressor miRNA in acute myeloid leukemia with prognostic implications. Exp Hematol Oncol. 2016 Feb 3;5:4. doi: 10.1186/s40164-016-0033-6. eCollection 2015. [Article]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. Richardson PG, Harvey RD, Laubach JP, Moreau P, Lonial S, San-Miguel JF: Panobinostat for the treatment of relapsed or relapsed/refractory multiple myeloma: pharmacology and clinical outcomes. Expert Rev Clin Pharmacol. 2016;9(1):35-48. doi: 10.1586/17512433.2016.1096773. Epub 2015 Oct 26. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Inhibitor
General Function
Steroid hydroxylase activity
Specific Function
Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic...
Gene Name
CYP2D6
Uniprot ID
P10635
Uniprot Name
Cytochrome P450 2D6
Molecular Weight
55768.94 Da
References
  1. Richardson PG, Harvey RD, Laubach JP, Moreau P, Lonial S, San-Miguel JF: Panobinostat for the treatment of relapsed or relapsed/refractory multiple myeloma: pharmacology and clinical outcomes. Expert Rev Clin Pharmacol. 2016;9(1):35-48. doi: 10.1586/17512433.2016.1096773. Epub 2015 Oct 26. [Article]
  2. Bailey H, Stenehjem DD, Sharma S: Panobinostat for the treatment of multiple myeloma: the evidence to date. J Blood Med. 2015 Oct 8;6:269-76. doi: 10.2147/JBM.S69140. eCollection 2015. [Article]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Xenobiotic-transporting atpase activity
Specific Function
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name
ABCB1
Uniprot ID
P08183
Uniprot Name
Multidrug resistance protein 1
Molecular Weight
141477.255 Da
References
  1. Bailey H, Stenehjem DD, Sharma S: Panobinostat for the treatment of multiple myeloma: the evidence to date. J Blood Med. 2015 Oct 8;6:269-76. doi: 10.2147/JBM.S69140. eCollection 2015. [Article]

Drug created at March 19, 2008 16:40 / Updated at December 02, 2023 07:01