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

Similar Structures

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)

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Associated Conditions

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	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

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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

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
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Abametapir	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.
Adagrasib	The serum concentration of Sonidegib can be increased when it is combined with Adagrasib.
Adalimumab	The metabolism of Sonidegib can be increased when combined with Adalimumab.
Albendazole	The metabolism of Sonidegib can be decreased when combined with Albendazole.
Aldesleukin	The serum concentration of Sonidegib can be increased when it is combined with Aldesleukin.
Alpelisib	The metabolism of Sonidegib can be increased when combined with Alpelisib.

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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

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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
Odomzo	Capsule	200 mg	Oral	Sun Pharmaceutical Industries (Europe) B.V.	2016-09-08	Not applicable
Odomzo	Capsule	200 mg/1	Oral	Sun Pharmaceutical Industries, Inc.	2017-09-21	Not applicable
Odomzo	Capsule	200 mg	Oral	Sun Pharmaceutical Industries (Europe) B.V.	2016-09-08	Not applicable
Odomzo	Capsule	200 mg/1	Oral	Novartis	2015-07-24	2017-12-31
Odomzo	Capsule	200 mg	Oral	Sun Pharmaceutical Industries Ltd.	2020-12-23	Not applicable

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
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

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
2	Completed	Treatment	Treatment for Basal Cell Carcinomas (BCCs) in Gorlin Syndrome Patients	1
2	Recruiting	Health Services Research	Medulloblastomas	1
2	Recruiting	Treatment	Basal Cell Carcinoma (BCC)	1
2	Recruiting	Treatment	Basal Cell Carcinoma (BCC) / Basal Cell Carcinoma of Skin, Site Unspecified / Cancer of the Skin / Invasive Carcinoma	1
2	Recruiting	Treatment	Locally Advanced Basal Cell Carcinoma	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Capsule	Oral	200 mg
Capsule	Oral	200 mg/1

Prices

Not Available

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)
US8178563	No	2012-05-15	2029-02-06
US8063043	No	2011-11-22	2029-09-15
US10266523	No	2019-04-23	2036-03-30

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	Not Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)	Predicted LC-MS/MS	Not Available

Targets

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Details1. Smoothened homolog

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

Details1. Cytochrome P450 3A4

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 September 28, 2023 01:14

Sonidegib

Identification

Structure for Sonidegib (DB09143)

Pharmacology

Interactions

Products

Categories

Chemical Identifiers

References

Clinical Trials

Pharmacoeconomics

Properties

Spectra

Targets

References

Enzymes

References