Givinostat
Identification
- Summary
Givinostat is a histone deacetylase inhibitor indicated for the treatment of Duchenne Muscular Dystrophy (DMD).
- Generic Name
- Givinostat
- DrugBank Accession Number
- DB12645
- Background
Givinostat is a small molecule histone deacetylase (HDAC) inhibitor. It has been investigated as a treatment for a variety of inflammatory diseases, like Crohn's disease and juvenile idiopathic arthritis, cancers like leukemia and lymphoma, as well as several muscular dystrophies. In the context of muscular dystrophy, inhibitors of HDAC appear to exert their therapeutic effects by targeting pathogenic processes that cause inflammation and muscle loss.4,1
Givinostat was granted FDA approval in March 2024 for the treatment of patients ≥6 years of age with Duchenne muscular dystrophy (DMD).3,4 It is the first non-steroidal drug approved to treat patients with all genetic variants of DMD.4
- Type
- Small Molecule
- Groups
- Approved, Investigational
- Structure
- Weight
- Average: 421.497
Monoisotopic: 421.200156361 - Chemical Formula
- C24H27N3O4
- Synonyms
- Givinostat
- External IDs
- ITF-2357
- ITF2357
Pharmacology
- Indication
Givinostat is indicated for the treatment of Duchenne muscular dystrophy (DMD) in patients ≥6 years of age.3
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Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Treatment of Duchenne muscular dystrophy (dmd) •••••••••••• •••••••••• - Contraindications & Blackbox Warnings
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- Pharmacodynamics
The efficacy givinostat was demonstrated in a randomized, double-blind, placebo-controlled trial wherein muscle function was evaluated by measuring the change from baseline to 18 months in the time taken to ascend four stairs. Patients treated with givinostat showed statistically significant less decline in the time it took to climb four stairs compared to placebo - the mean change was 1.25 seconds for patients receiving givinostat compared to 3.03 seconds for patients receiving placebo.3,4
Givinostat causes QTc interval prolongation and should be used with caution in patients with underlying cardiac disease or in patients who are taking concomitant medications that may prolong the QT interval.3
- Mechanism of action
Givinostat is a histone deacetylase inhibitor. The precise mechanism by which givinostat exerts its therapeutic effects in patients with DMD is unknown.3
Histone deacetylases (HDACs), as the name implies, regulate the deacetylation of various proteins. The acetylation and deacetylation of histone proteins causes an increase or decrease in gene expression, respectively, with the latter function governed by HDACs. The balance between levels of histone acetylation and deacetylation plays a key role in the modulation of gene transcription and governs numerous developmental processes, being involved in the regulation of various genes associated with signal transduction, cell growth, and cell death, as well as diseases like cancers.1 HDACs can deacetylate non-histone proteins, such as p53, thereby also regulating their activity.1
Several HDAC isoforms have been implicated in skeletal muscle remodeling - under both physiological and pathological conditions - which serve to regulate fiber type specification, muscle fiber size and innervation, metabolic fuel switching, muscle development, insulin sensitivity, and exercise capacity.1 This gave rise to interest in HDACs as a potential target in the treatment of muscular dystrophies, including Duchenne Muscular Dystrophy (DMD). Consistently, HDAC expression and activity have been found altered in muscular dystrophies, suggesting a role for these enzymes in the progression of the disease.1 The inhibition of these enzymes by HDAC inhibitors such as givinostat contributes to the preservation of muscle force and morphology.1
Target Actions Organism AHistone deacetylase inhibitorHumans - Absorption
The absolute bioavailability of givinostat has not been determined. The Tmax of givinostat occurs approximately 2-3 hours following oral administration, and steady-state is achieved within 5 to 7 days with twice daily dosing.3 Systemic exposure is proportional to the administered dose across the therapeutic dose range.
Administration with a high-fat meal resulted in a 40% increase in AUC, a 23% increase in Cmax, and a delay in Tmax of 2-3 hours.3
- Volume of distribution
According to population pharmacokinetic modeling, the estimated apparent volume of distribution of the central compartment is 160 L.2 The estimated apparent volume of distribution of the peripheral compartment is 483 L.2
- Protein binding
Givinostat is highly (~96%) protein bound in plasma.3
- Metabolism
Givinostat is extensively metabolized to several metabolites, four of which have been characterized: ITF2374, ITF2375, ITF2440, and ITF2563.3 These metabolites do not contribute to the efficacy of givinostat.3 The enzymes responsible for the metabolism of givinostat are unclear; its metabolism is not mediated by CYP450 or UGT enzymes.3
- Route of elimination
Urinary excretion of givinostat is minimal (<3%).3 The elimination of givinostat is likely driven by metabolism followed by renal and biliary excretion of the resulting metabolites.3
- Half-life
The apparent plasma elimination half-life of givinostat is approximately 6 hours.3
- Clearance
According to population pharmacokinetic modeling, the estimated apparent oral clearance of givinostat is 121 L/h.2 The estimated compartmental clearance of givinostat is 33.8 L/h.2
- Adverse Effects
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- Toxicity
There are no data available regarding overdosage with givinostat. In healthy subjects administered a dose of 265.8 mg (approximately 5-fold the 53.2 mg dose recommended for DMD patients weighing 60 kg or more), an increase in QTc interval 5 hours post-administration was observed, the largest mean increase being 13.6 ms.3
- 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.
Drug Interaction Integrate drug-drug
interactions in your softwareAbemaciclib The serum concentration of Abemaciclib can be increased when it is combined with Givinostat. Acalabrutinib The serum concentration of Acalabrutinib can be increased when it is combined with Givinostat. Acebutolol The risk or severity of QTc prolongation can be increased when Acebutolol is combined with Givinostat. Acenocoumarol The serum concentration of Acenocoumarol can be increased when it is combined with Givinostat. Acrivastine The risk or severity of QTc prolongation can be increased when Acrivastine is combined with Givinostat. - Food Interactions
- Take with food. Prescribing information for givinostat recommends it be administered with food twice daily.
Products
- Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.
- Product Ingredients
Ingredient UNII CAS InChI Key Givinostat hydrochloride monohydrate Not Available Not Available Not applicable - Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Duvyzat Suspension 8.86 mg/1mL Oral Italfarmaco SpA 2024-03-21 Not applicable US
Categories
- Drug Categories
- Acids, Acyclic
- Amines
- Antineoplastic Agents
- Cytochrome P-450 CYP1A2 Inducers
- Cytochrome P-450 CYP1A2 Inducers (strength unknown)
- Cytochrome P-450 CYP2B6 Inducers
- Cytochrome P-450 CYP2B6 Inducers (strength unknown)
- Cytochrome P-450 CYP3A Inducers
- Cytochrome P-450 CYP3A Inhibitors
- Cytochrome P-450 CYP3A4 Inducers
- Cytochrome P-450 CYP3A4 Inducers (strength unknown)
- Cytochrome P-450 CYP3A4 Inhibitors
- Cytochrome P-450 CYP3A4 Inhibitors (strength unknown)
- Cytochrome P-450 Enzyme Inducers
- Cytochrome P-450 Enzyme Inhibitors
- Enzyme Inhibitors
- Histone Deacetylase Inhibitors
- Hydroxy Acids
- Hydroxylamines
- OCT2 Inhibitors
- Potential QTc-Prolonging Agents
- QTc Prolonging Agents
- Chemical TaxonomyProvided by Classyfire
- Description
- This compound belongs to the class of organic compounds known as phenylcarbamic acid esters. These are ester derivatives of phenylcarbamic acids.
- Kingdom
- Organic compounds
- Super Class
- Benzenoids
- Class
- Benzene and substituted derivatives
- Sub Class
- Phenylcarbamic acid esters
- Direct Parent
- Phenylcarbamic acid esters
- Alternative Parents
- Naphthalenes / Benzoic acids and derivatives / Benzoyl derivatives / Aralkylamines / Carbamate esters / Trialkylamines / Organic carbonic acids and derivatives / Hydroxamic acids / Organopnictogen compounds / Organic oxides show 2 more
- Substituents
- Amine / Amino acid or derivatives / Aralkylamine / Aromatic homopolycyclic compound / Benzoic acid or derivatives / Benzoyl / Carbamic acid ester / Carbonic acid derivative / Carbonyl group / Carboxylic acid derivative show 12 more
- Molecular Framework
- Aromatic homopolycyclic compounds
- External Descriptors
- Not Available
- Affected organisms
- Humans
Chemical Identifiers
- UNII
- 5P60F84FBH
- CAS number
- 497833-27-9
- InChI Key
- YALNUENQHAQXEA-UHFFFAOYSA-N
- InChI
- InChI=1S/C24H27N3O4/c1-3-27(4-2)15-17-5-7-21-14-18(6-8-20(21)13-17)16-31-24(29)25-22-11-9-19(10-12-22)23(28)26-30/h5-14,30H,3-4,15-16H2,1-2H3,(H,25,29)(H,26,28)
- IUPAC Name
- {6-[(diethylamino)methyl]naphthalen-2-yl}methyl N-[4-(hydroxycarbamoyl)phenyl]carbamate
- SMILES
- CCN(CC)CC1=CC=C2C=C(COC(=O)NC3=CC=C(C=C3)C(=O)NO)C=CC2=C1
References
- General References
- Sandona M, Cavioli G, Renzini A, Cedola A, Gigli G, Coletti D, McKinsey TA, Moresi V, Saccone V: Histone Deacetylases: Molecular Mechanisms and Therapeutic Implications for Muscular Dystrophies. Int J Mol Sci. 2023 Feb 21;24(5):4306. doi: 10.3390/ijms24054306. [Article]
- Fiorentini F, Germani M, Del Bene F, Pellizzoni C, Cazzaniga S, Rocchetti M, Bettica P: Population pharmacokinetic-pharmacodynamic analysis of givinostat. Expert Opin Drug Metab Toxicol. 2023 Apr;19(4):229-238. doi: 10.1080/17425255.2023.2219839. Epub 2023 Jun 12. [Article]
- FDA Approved Drug Products: Duvyzat (givinostat) suspension for oral administration [Link]
- FDA Press Announcement: FDA Approves Nonsteroidal Treatment for Duchenne Muscular Dystrophy [Link]
- External Links
- Human Metabolome Database
- HMDB0252732
- PubChem Compound
- 9804992
- PubChem Substance
- 347828853
- ChemSpider
- 7980752
- BindingDB
- 50105329
- 2678889
- ChEBI
- 94187
- ChEMBL
- CHEMBL1213492
- ZINC
- ZINC000003820616
- PDBe Ligand
- QCM
- Wikipedia
- Givinostat
- PDB Entries
- 6uoc
Clinical Trials
- Clinical Trials
Phase Status Purpose Conditions Count 3 Completed Treatment Duchenne Muscular Dystrophy (DMD) 1 3 Recruiting Treatment Duchenne Muscular Dystrophy (DMD) 1 3 Recruiting Treatment Polycythemia Vera (PV) 1 2 Active Not Recruiting Treatment Chronic Myeloproliferative Neoplasms 1 2 Completed Treatment Active Systemic / Onset Juvenile Idiopathic Arthritis 1
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Suspension Oral 8.86 mg/1mL - Prices
- Not Available
- Patents
- Not Available
Properties
- State
- Solid
- Experimental Properties
- Not Available
- Predicted Properties
Property Value Source Water Solubility 0.0052 mg/mL ALOGPS logP 4.18 ALOGPS logP 3.51 Chemaxon logS -4.9 ALOGPS pKa (Strongest Acidic) 9.99 Chemaxon pKa (Strongest Basic) 9.35 Chemaxon Physiological Charge 1 Chemaxon Hydrogen Acceptor Count 5 Chemaxon Hydrogen Donor Count 3 Chemaxon Polar Surface Area 90.9 Å2 Chemaxon Rotatable Bond Count 9 Chemaxon Refractivity 122.49 m3·mol-1 Chemaxon Polarizability 47.59 Å3 Chemaxon Number of Rings 3 Chemaxon Bioavailability 1 Chemaxon Rule of Five Yes Chemaxon Ghose Filter Yes Chemaxon Veber's Rule No Chemaxon MDDR-like Rule Yes Chemaxon - Predicted ADMET Features
- Not Available
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
Spectrum Spectrum Type Splash Key Predicted MS/MS Spectrum - 10V, Positive (Annotated) Predicted LC-MS/MS splash10-00bi-3598500000-bf58ce314e74324de79e Predicted MS/MS Spectrum - 10V, Negative (Annotated) Predicted LC-MS/MS splash10-0uds-2900100000-503630a28f39f2cc87c2 Predicted MS/MS Spectrum - 20V, Negative (Annotated) Predicted LC-MS/MS splash10-000f-5900000000-ffd05267507bdcaa3377 Predicted MS/MS Spectrum - 20V, Positive (Annotated) Predicted LC-MS/MS splash10-00kr-1439100000-919c118261cc4c1cadf0 Predicted MS/MS Spectrum - 40V, Positive (Annotated) Predicted LC-MS/MS splash10-0pb9-1901000000-def3c6e6b87bebfc6cad Predicted MS/MS Spectrum - 40V, Negative (Annotated) Predicted LC-MS/MS splash10-0006-5921000000-ccc9be85c65b98d72033 Predicted 1H NMR Spectrum 1D NMR Not Applicable Predicted 13C NMR Spectrum 1D NMR Not Applicable - Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 225.6468489 predictedDarkChem Lite v0.1.0 [M-H]- 203.70831 predictedDeepCCS 1.0 (2019) [M+H]+ 226.2010489 predictedDarkChem Lite v0.1.0 [M+H]+ 206.06631 predictedDeepCCS 1.0 (2019) [M+Na]+ 225.6820489 predictedDarkChem Lite v0.1.0 [M+Na]+ 213.90892 predictedDeepCCS 1.0 (2019)
Targets
- 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
- Arya Y, Syal A, Gupta M, Gaba S: Advances in the Treatment of Polycythemia Vera: Trends in Disease Management. Cureus. 2021 Mar 30;13(3):e14193. doi: 10.7759/cureus.14193. [Article]
- Curreli F, Ahmed S, Victor SMB, Debnath AK: Identification of Combinations of Protein Kinase C Activators and Histone Deacetylase Inhibitors That Potently Reactivate Latent HIV. Viruses. 2020 Jun 3;12(6). pii: v12060609. doi: 10.3390/v12060609. [Article]
Enzymes
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- InhibitorInducer
- 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
- FDA Approved Drug Products: Duvyzat (givinostat) suspension for oral administration [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Inducer
- General Function
- Oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen
- 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 oxidizes a variety of structurally un...
- Gene Name
- CYP1A2
- Uniprot ID
- P05177
- Uniprot Name
- Cytochrome P450 1A2
- Molecular Weight
- 58293.76 Da
References
- FDA Approved Drug Products: Duvyzat (givinostat) suspension for oral administration [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Inducer
- General Function
- Steroid 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 oxidizes a variety of structurally un...
- Gene Name
- CYP2B6
- Uniprot ID
- P20813
- Uniprot Name
- Cytochrome P450 2B6
- Molecular Weight
- 56277.81 Da
References
- FDA Approved Drug Products: Duvyzat (givinostat) suspension for oral administration [Link]
Transporters
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Inhibitor
- General Function
- Quaternary ammonium group transmembrane transporter activity
- Specific Function
- Mediates tubular uptake of organic compounds from circulation. Mediates the influx of agmatine, dopamine, noradrenaline (norepinephrine), serotonin, choline, famotidine, ranitidine, histamin, creat...
- Gene Name
- SLC22A2
- Uniprot ID
- O15244
- Uniprot Name
- Solute carrier family 22 member 2
- Molecular Weight
- 62579.99 Da
References
- FDA Approved Drug Products: Duvyzat (givinostat) suspension for oral administration [Link]
Drug created at October 20, 2016 23:24 / Updated at April 08, 2024 21:18