Sonidegib
Identification
- Summary
Sonidegib is an antineoplastic agent used for the treatment of locally advanced recurrent basal cell carcinoma (BCC) following surgery and radiation therapy, or in cases where surgery or radiation therapy are not appropriate.
- Brand Names
- Odomzo
- Generic Name
- Sonidegib
- DrugBank Accession Number
- DB09143
- Background
Sonidegib is a Hedgehog signaling pathway inhibitor (via smoothened antagonism) developed as an anticancer agent by Novartis. It was FDA approved in 2015 for the treatment of basal cell carcinoma.
- Type
- Small Molecule
- Groups
- Approved, Investigational
- Structure
- Weight
- Average: 485.507
Monoisotopic: 485.192626198 - Chemical Formula
- C26H26F3N3O3
- Synonyms
- Erismodegib
- N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridin-3-yl]-2-methyl-4'-(trifluoromethoxy)[1,1'-biphenyl]-3-carboxamide
- Sonidegib
- External IDs
- LDE 225
- LDE-225
- LDE225
- NVP-LDE 225
- NVP-LDE-225
- NVP-LDE225
Pharmacology
- Indication
Sonidegib is approved for use in the US and EU for treatment of adults with locally advanced basal cell carcinoma (BCC) that has recurred post surgery or radiation therapy. It is also approved for adult patients with BCC who are not eligible for surgery or radiation therapy. (2)
Reduce drug development failure ratesBuild, train, & validate machine-learning modelswith evidence-based and structured datasets.Build, train, & validate predictive machine-learning models with structured datasets.- Associated Conditions
Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Treatment of Refractory, locally advanced basal cell carcinoma •••••••••••• ••••• - Contraindications & Blackbox Warnings
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- Pharmacodynamics
Sonidegib has been shown to inhibit a transmembrane protein called SMO which plays a role in Hh signal transduction. This has resulted in inhibition of Hh signaling as well as antitumour activity in various animal models. In a transgenic mouse model of islet cell neoplasms, tumour volume was reduce by 95% in mice treated with sonidegib when compared with untreated mice. (2)
- Mechanism of action
The hedgehog pathway is involved in many human cancers. Sonidegib effectively inhibits the regulator called smoothened (Smo), preventing the hedgehog pathway from functioning. As a result, tumours that depend on the hedgehog pathway are unable to grow. (1)
Target Actions Organism USmoothened homolog antagonistHumans - Absorption
Sonidegib is rapidly absorbed in the fasted state with peak concentrations occurring 2-4 hours after administration. (2) However, the total absorption of Sonidegib is low (roughly 6-7%). (1)
- Volume of distribution
Estimated volume of distribution = 9166 L (2)
- Protein binding
Sonidegib is over 97% bound to plasma proteins, and binding is independent of concentration. (2)
- Metabolism
Sonidegib is primarily metabolized via oxidation and amide hydrolysis. (1) The enzyme responsible for the majority of metabolism is the cytochrome P450 (CYP) 3A4 enzyme. (2)
- Route of elimination
Around 70% of Sonidegib is eliminated in the feces, while 30% is eliminated in the urine. (2)
- Half-life
Half-life ~ 28 days (2)
- Clearance
Not Available
- Adverse Effects
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- Toxicity
Adverse events occurred more frequently with higher doses, 800 mg once daily when compared to a lower dose of 200 mg once daily. In the 200 mg group, frequent adverse events (occurring in ≥2% of patients) included: elevated creatine phosphokinase (6%), increased lipase (5%), muscle spasms (3%), asthenia (3%), and hypertension (3%). In the 800 mg group, frequent adverse events included: elevated creatine phosphokinase (13%), increased lipase (5%), weight loss (5%), muscle spasms (5%), decreased appetite (4%), rhabdomyolysis (3%), nausea (3%), hypertension (3%), increased alanine aminotransferase (3%), increased aspartate aminotransferase (3%), fatigue (2%), syncope (2%), anaemia (2%), dehydration (2%), hyperkalaemia (2%) and myalgia (2%). Rhabdomyolysis cases reported by investigators were not confirmed by the adjudication committee on muscle toxicity or the independent safety review. (2)
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs Browse all" title="About SNP Mediated Effects/ADRs" id="snp-actions-info" class="drug-info-popup" href="javascript:void(0);">
- Not Available
Interactions
- Drug Interactions Learn More" title="About Drug Interactions" id="structured-interactions-info" class="drug-info-popup" href="javascript:void(0);">
- 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 softwareAbametapir The serum concentration of Sonidegib can be increased when it is combined with Abametapir. Abatacept The metabolism of Sonidegib can be increased when combined with Abatacept. Acalabrutinib The metabolism of Sonidegib can be decreased when combined with Acalabrutinib. Acetaminophen The metabolism of Sonidegib can be increased when combined with Acetaminophen. Acetazolamide The serum concentration of Sonidegib can be increased when it is combined with Acetazolamide. - Food Interactions
- Exercise caution with grapefruit products. Grapefruit inhibits the CYP3A metabolism of sonidegib, which may increase its serum concentration.
- Exercise caution with St. John's Wort. This herb induces the CYP3A metabolism of sonidegib, which may reduce its serum concentration.
- Take on an empty stomach. Take sonidegib at least 1 hour before or 2 hours after eating.
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 Sonidegib phosphate W421AI34UW 1218778-77-8 RWIVSVMMGFFZIJ-VWDRLOGHSA-N - Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Odomzo Capsule 200 mg Oral Sun Pharmaceutical Industries (Europe) B.V. 2016-09-08 Not applicable EU Odomzo Capsule 200 mg/1 Oral Novartis 2015-07-24 2017-12-31 US Odomzo Capsule 200 mg Oral Sun Pharmaceutical Industries Ltd. 2020-12-23 Not applicable Canada Odomzo Capsule 200 mg Oral Sun Pharmaceutical Industries (Europe) B.V. 2016-09-08 Not applicable EU Odomzo Capsule 200 mg/1 Oral Sun Pharmaceutical Industries, Inc. 2017-09-21 Not applicable US
Categories
- ATC Codes
- L01XJ02 — Sonidegib
- Drug Categories
- Antineoplastic Agents
- Antineoplastic and Immunomodulating Agents
- Benzene Derivatives
- Cytochrome P-450 CYP3A Substrates
- Cytochrome P-450 CYP3A4 Substrates
- Cytochrome P-450 CYP3A4 Substrates with a Narrow Therapeutic Index
- Cytochrome P-450 Substrates
- Hedgehog Pathway Inhibitor
- Hedgehog pathway inhibitors
- Narrow Therapeutic Index Drugs
- Smoothened Receptor Antagonists
- Chemical TaxonomyProvided by Classyfire
- Description
- This compound belongs to the class of organic compounds known as biphenyls and derivatives. These are organic compounds containing to benzene rings linked together by a C-C bond.
- Kingdom
- Organic compounds
- Super Class
- Benzenoids
- Class
- Benzene and substituted derivatives
- Sub Class
- Biphenyls and derivatives
- Direct Parent
- Biphenyls and derivatives
- Alternative Parents
- o-Toluamides / Benzamides / Phenoxy compounds / Phenol ethers / Benzoyl derivatives / Dialkylarylamines / Aminopyridines and derivatives / Imidolactams / Morpholines / Heteroaromatic compounds show 10 more
- Substituents
- Alkyl fluoride / Alkyl halide / Aminopyridine / Aromatic heteromonocyclic compound / Azacycle / Benzamide / Benzoic acid or derivatives / Benzoyl / Biphenyl / Carboxamide group show 28 more
- Molecular Framework
- Aromatic heteromonocyclic compounds
- External Descriptors
- Not Available
- Affected organisms
- Not Available
Chemical Identifiers
- UNII
- 0RLU3VTK5M
- CAS number
- 956697-53-3
- InChI Key
- VZZJRYRQSPEMTK-CALCHBBNSA-N
- InChI
- InChI=1S/C26H26F3N3O3/c1-16-14-32(15-17(2)34-16)24-12-9-20(13-30-24)31-25(33)23-6-4-5-22(18(23)3)19-7-10-21(11-8-19)35-26(27,28)29/h4-13,16-17H,14-15H2,1-3H3,(H,31,33)/t16-,17+
- IUPAC Name
- N-{6-[(2R,6S)-2,6-dimethylmorpholin-4-yl]pyridin-3-yl}-2-methyl-4'-(trifluoromethoxy)-[1,1'-biphenyl]-3-carboxamide
- SMILES
- [H][C@]1(C)CN(C[C@@]([H])(C)O1)C1=CC=C(NC(=O)C2=CC=CC(=C2C)C2=CC=C(OC(F)(F)F)C=C2)C=N1
References
- General References
- Zollinger M, Lozac'h F, Hurh E, Emotte C, Bauly H, Swart P: Absorption, distribution, metabolism, and excretion (ADME) of (1)(4)C-sonidegib (LDE225) in healthy volunteers. Cancer Chemother Pharmacol. 2014 Jul;74(1):63-75. doi: 10.1007/s00280-014-2468-y. Epub 2014 May 10. [Article]
- Burness CB: Sonidegib: First Global Approval. Drugs. 2015 Sep;75(13):1559-66. doi: 10.1007/s40265-015-0458-y. [Article]
- FDA Approved Drug Products: ODOMZO (sonidegib) capsules [Link]
- External Links
- KEGG Drug
- D10119
- PubChem Compound
- 24775005
- PubChem Substance
- 310265056
- ChemSpider
- 25027390
- BindingDB
- 50394562
- 1659191
- ChEBI
- 90863
- ChEMBL
- CHEMBL2105737
- ZINC
- ZINC000068202099
- RxList
- RxList Drug Page
- Drugs.com
- Drugs.com Drug Page
- Wikipedia
- Sonidegib
- FDA label
- Download (428 KB)
- MSDS
- Download (59.6 KB)
Clinical Trials
- Clinical Trials Learn More" title="About Clinical Trials" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">
Phase Status Purpose Conditions Count 2 Completed Treatment Acute Leukemia 1 2 Completed Treatment Basal Cell Carcinoma (BCC) 1 2 Completed Treatment Basal Cell Carcinoma (BCC) / Nevoid Basal Cell Carcinoma (BCC) Syndrome 1 2 Completed Treatment Medulloblastomas 1 2 Completed Treatment Recurrent Plasma Cell Myeloma / Refractory Plasma Cell Myeloma 1
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Capsule Oral 200 mg/1 Capsule Oral 200 mg - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US8178563 No 2012-05-15 2029-02-06 US US8063043 No 2011-11-22 2029-09-15 US US10266523 No 2019-04-23 2036-03-30 US
Properties
- State
- Solid
- Experimental Properties
- Not Available
- Predicted Properties
Property Value Source Water Solubility 0.00155 mg/mL ALOGPS logP 5.64 ALOGPS logP 6.76 Chemaxon logS -5.5 ALOGPS pKa (Strongest Acidic) 14.21 Chemaxon pKa (Strongest Basic) 5.45 Chemaxon Physiological Charge 0 Chemaxon Hydrogen Acceptor Count 5 Chemaxon Hydrogen Donor Count 1 Chemaxon Polar Surface Area 63.69 Å2 Chemaxon Rotatable Bond Count 6 Chemaxon Refractivity 125.34 m3·mol-1 Chemaxon Polarizability 49.91 Å3 Chemaxon Number of Rings 4 Chemaxon Bioavailability 1 Chemaxon Rule of Five No Chemaxon Ghose Filter No 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 splash10-000i-0000900000-cc64530a4d2866d571c0 Predicted MS/MS Spectrum - 10V, Negative (Annotated) Predicted LC-MS/MS splash10-001i-0010900000-84f766cc943388ab159b Predicted MS/MS Spectrum - 20V, Positive (Annotated) Predicted LC-MS/MS splash10-004i-0000900000-60079b9eeeea69cc5269 Predicted MS/MS Spectrum - 20V, Negative (Annotated) Predicted LC-MS/MS splash10-0096-2000900000-8dbecd1442d65246206b Predicted MS/MS Spectrum - 40V, Positive (Annotated) Predicted LC-MS/MS splash10-005i-0253900000-42495b36f26383cfe5aa Predicted MS/MS Spectrum - 40V, Negative (Annotated) Predicted LC-MS/MS splash10-02ai-0923800000-fbf9b47f0d549f224c6a 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]- 206.66583 predictedDeepCCS 1.0 (2019) [M+H]+ 208.89107 predictedDeepCCS 1.0 (2019) [M+Na]+ 214.8036 predictedDeepCCS 1.0 (2019)
Targets
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Antagonist
- General Function
- Wnt-protein binding
- Specific Function
- G protein-coupled receptor that probably associates with the patched protein (PTCH) to transduce the hedgehog's proteins signal. Binding of sonic hedgehog (SHH) to its receptor patched is thought t...
- Gene Name
- SMO
- Uniprot ID
- Q99835
- Uniprot Name
- Smoothened homolog
- Molecular Weight
- 86395.95 Da
References
- Burness CB: Sonidegib: First Global Approval. Drugs. 2015 Sep;75(13):1559-66. doi: 10.1007/s40265-015-0458-y. [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
- Burness CB: Sonidegib: First Global Approval. Drugs. 2015 Sep;75(13):1559-66. doi: 10.1007/s40265-015-0458-y. [Article]
Drug created at October 01, 2015 15:13 / Updated at February 20, 2024 23:54