Identification

Name
Sonidegib
Accession Number
DB09143
Description

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
Thumb
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)

Associated Conditions
Contraindications & Blackbox Warnings
Learn about our commercial Contraindications & Blackbox Warnings data.
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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)

TargetActionsOrganism
USmoothened homolog
antagonist
Humans
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
Learn about our commercial Adverse Effects data.
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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)

Affected organisms
Not Available
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 Sonidegib can be increased when it is combined with Abametapir.
AbataceptThe metabolism of Sonidegib can be increased when combined with Abatacept.
AcalabrutinibThe metabolism of Sonidegib can be decreased when combined with Acalabrutinib.
AcetaminophenThe metabolism of Sonidegib can be increased when combined with Acetaminophen.
AcetazolamideThe metabolism of Sonidegib can be decreased when combined with Acetazolamide.
AdalimumabThe metabolism of Sonidegib can be increased when combined with Adalimumab.
AlbendazoleThe metabolism of Sonidegib can be decreased when combined with Albendazole.
AldesleukinThe metabolism of Sonidegib can be decreased when combined with Aldesleukin.
AlpelisibThe metabolism of Sonidegib can be increased when combined with Alpelisib.
AminoglutethimideThe metabolism of Sonidegib can be increased when combined with Aminoglutethimide.
Additional Data Available
  • Extended Description
    Extended Description

    Extended description of the mechanism of action and particular properties of each drug interaction.

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  • Severity
    Severity

    A severity rating for each drug interaction, from minor to major.

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  • Evidence Level
    Evidence Level

    A rating for the strength of the evidence supporting each drug interaction.

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  • Action
    Action

    An effect category for each drug interaction. Know how this interaction affects the subject drug.

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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

Product Ingredients
IngredientUNIICASInChI Key
Sonidegib phosphateW421AI34UW1218778-77-8RWIVSVMMGFFZIJ-VWDRLOGHSA-N
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
OdomzoCapsule200 mg/1OralSun Pharmaceutical Industries, Inc.2017-09-21Not applicableUS flag
OdomzoCapsule200 mgOralSun Pharmaceutical Industries (Europe) B.V.2015-08-14Not applicableEU flag
OdomzoCapsule200 mg/1OralNovartis2015-07-242017-12-31US flag
OdomzoCapsule200 mgOralSun Pharmaceutical Industries (Europe) B.V.2015-08-14Not applicableEU flag
Additional Data Available
  • Application Number
    Application Number

    A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

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  • Product Code
    Product Code

    A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

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Categories

ATC Codes
L01XX48 — Sonidegib
Drug Categories
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

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][[email protected]]1(C)CN(C[[email protected]@]([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
  1. 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. [PubMed:24817600]
  2. Burness CB: Sonidegib: First Global Approval. Drugs. 2015 Sep;75(13):1559-66. doi: 10.1007/s40265-015-0458-y. [PubMed:26323341]
KEGG Drug
D10119
PubChem Compound
24775005
PubChem Substance
310265056
ChemSpider
25027390
BindingDB
50394562
RxNav
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
PhaseStatusPurposeConditionsCount
2Active Not RecruitingTreatmentRecurrent Plasma Cell Myeloma / Refractory Plasma Cell Myeloma1
2CompletedTreatmentBasal Cell Carcinoma (BCC)1
2CompletedTreatmentBasal Cell Carcinoma (BCC) / Gorlin's Syndrome / Nevoid Basal Cell Carcinoma Syndrome1
2CompletedTreatmentLeukemia, Acute1
2CompletedTreatmentMedulloblastomas1
2CompletedTreatmentTreatment for Basal Cell Carcinomas (BCCs) in Gorlin Syndrome Patients1
2RecruitingTreatmentBasal Cell Carcinoma (BCC) / Basal Cell Carcinoma of Skin, Site Unspecified / Invasive Carcinoma / Skin Cancers1
2TerminatedTreatmentBasal Cell Carcinoma (BCC) / Basal Cell Carcinoma (BCC) of the Skin / Basal Cell Carcinoma of the Skin / Basal Cell Nevus Syndrome / Nevoid Basal Cell Carcinoma (BCC) Syndrome / Nevoid Basal Cell Carcinoma Syndrome / Recurrent Skin Cancer / Skin Neoplasms1
2TerminatedTreatmentMultiple Myeloma (MM)1
2TerminatedTreatmentPTCH1 or SMO Activated Solid and Hematologic Tumors1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
CapsuleOral200 mg/1
CapsuleOral200 mg
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US8178563No2012-05-152029-02-06US flag
US8063043No2011-11-222029-09-15US flag
Additional Data Available
  • Filed On
    Filed On

    The date on which a patent was filed with the relevant government.

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Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.00155 mg/mLALOGPS
logP5.64ALOGPS
logP6.76ChemAxon
logS-5.5ALOGPS
pKa (Strongest Acidic)14.21ChemAxon
pKa (Strongest Basic)5.45ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area63.69 Å2ChemAxon
Rotatable Bond Count6ChemAxon
Refractivity125.34 m3·mol-1ChemAxon
Polarizability49.91 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
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/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

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
  1. Burness CB: Sonidegib: First Global Approval. Drugs. 2015 Sep;75(13):1559-66. doi: 10.1007/s40265-015-0458-y. [PubMed:26323341]

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. Burness CB: Sonidegib: First Global Approval. Drugs. 2015 Sep;75(13):1559-66. doi: 10.1007/s40265-015-0458-y. [PubMed:26323341]

Drug created on October 01, 2015 09:13 / Updated on July 07, 2020 16:27

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