Osilodrostat

Identification

Summary

Osilodrostat is an oral inhibitor of cortisol synthesis used to treat Cushing's disease by normalizing hypercortisolism.

Brand Names

Isturisa

Generic Name

Osilodrostat

DrugBank Accession Number

DB11837

Background

Osilodrostat is an inhibitor of 11β-hydroxylase (also referred to as CYP11B1), the enzyme that catalyzes the final step in the biosynthesis of endogenous cortisol.⁶ It is used to lower circulating cortisol levels in the treatment of Cushing's disease, a disorder in which cortisol levels are chronically and supraphysiologically elevated. Cushing's disease is often the result of ACTH hypersecretion secondary to a pituitary tumor, and surgical resection of the tumour is generally the treatment of choice.⁵ As an orally bioavailable drug therapy, osilodrostat provides a novel treatment option for patients in whom removal of the causative tumor is not an option or for whom previous pituitary surgery has not been curative.

Osilodrostat is manufactured by Novartis under the brand name Isturisa.⁶ It has undergone phase II clinical trials for the treatment of solid tumours, hypertension, and heart failure, but development for these indications was discontinued by Novartis in January 2013.⁴ Osilodrostat was approved for use in the EU in January 2020 for the treatment of endogenous Cushing's syndrome (i.e. Cushing's disease),⁴ and was granted FDA approval and Orphan Drug designation in the US in March 2020 for the same indication.⁹

Type

Small Molecule

Groups

Approved, Investigational

Structure

3D

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MOLSDF3D-SDFPDBSMILESInChI

Similar Structures

Structure for Osilodrostat (DB11837)

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Weight

Average: 227.242
Monoisotopic: 227.085875497

Chemical Formula

C₁₃H₁₀FN₃

Synonyms

• Osilodrostat

External IDs

• LCI 699
• LCI-699-NX
• LCI699
• LCI699-NX

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Pharmacology

Indication

Osilodrostat is indicated for the treatment of adult patients with Cushing's disease for whom pituitary surgery is not an option or has not been curative.^6,4

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Associated Conditions

Indication Type	Indication	Combined Product Details	Approval Level	Age Group	Patient Characteristics	Dose Form
Treatment of	Cushings disease		••••••••••••	•••••	••••••••• ••••••• •• ••• •• •••••• •• ••• ••• •••• ••••••••	••••••

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Pharmacodynamics

Osilodrostat lowers endogenous cortisol levels by inhibiting the enzyme that catalyzes the final step in cortisol synthesis.⁶ As endogenous cortisol levels function as a surrogate marker for drug effect, 24-hour urine free cortisol levels should be assessed 1-2x weekly during the initial titration stage and every 1-2 months thereafter to ensure cortisol levels remain physiologically appropriate.⁶ Osilodrostat is highly metabolized and requires dose adjustments in patient with hepatic dysfunction.⁶

Osilodrostat can cause a dose-dependent prolongation of the QTc interval and should be used with caution in patients with a higher baseline risk (e.g. concomitant QTc-prolonging medications, electrolyte abnormalities). Prior to beginning therapy, patients should have a baseline ECG and any electrolyte abnormalities (especially hypokalemia and/or hypomagnesemia) should be remedied.⁶

As osilodrostat halts cortisol synthesis at its final stage, its use can result in the accumulation of cortisol precursors, aldosterone precursors, and androgens. The accumulation of the cortisol precursor 11-deoxycorticosterone can activate mineralocorticoid receptors which may lead to hypokalemia, edema, or hypertension.⁶ Patients should be monitored for these symptoms as they are evidence of elevated 11-deoxycorticosterone levels, and for symptoms such as hirustism, acne, and hypertrichosis which may be suggestive of excessive circulating androgen levels.⁶

Mechanism of action

Cushing’s syndrome is an endocrine disorder resulting from chronic and excessive exposure to glucocorticoids, the symptoms of which may include thinning of the skin and hair, weight gain, muscle weakness, and osteoporosis, as well a constellation of psychiatric, cardiovascular, and immunological deficiencies.⁵ Cushing’s syndrome is most commonly precipitated by exogenous treatment with supraphysiological doses of glucocorticoids such as those found in nasal sprays, skin creams, and inhalers. Cushing’s disease - another less common cause of Cushing’s syndrome - is generally the result of increased endogenous cortisol exposure due to excessive secretion of adrenocroticotrophic hormone (ACTH) from a pituitary adenoma.⁵

Osilodrostat is an inhibitor of 11β-hydroxylase (CYP11B1) and, to a lesser extent, aldosterone synthase (CYP11B2).⁶ The CYP11B1 enzyme is responsible for catalyzing the final step of cortisol synthesis - by inhibiting this enzyme, osilodrostat helps to normalize endogenous cortisol levels and alleviate symptoms of Cushing’s disease.⁶

Target	Actions	Organism
ACytochrome P450 11B1, mitochondrial	inhibitor	Humans
NCytochrome P450 11B2, mitochondrial	inhibitor	Humans

Absorption

The oral absorption of osilodrostat is rapid, with a T_max of approximately 1 hour,⁶ and assumed to be essentially complete.⁷ Exposure (i.e. AUC and C_max) increases slightly more than dose-proportionately over the standard dosing range.⁷

Coadministration of osilodrostat with food does not affect its pharmacokinetics to a clinically significant extent.⁶ Age and gender do not affect pharmacokinetics, but bioavailability and total exposure is higher (though not clinically significant) in patients of Asian descent.⁶ Exposure to osilodrostat is greater in patients with moderate-severe hepatic impairment - prescribing information recommends a starting dose of 1mg twice daily in patients with moderate hepatic impairment (Child-Pugh B) and a starting dose of 1mg each evening in patients with severe hepatic impairment (Child-Pugh C).⁶

Volume of distribution

The median apparent volume of distribution of osilodrostat is 100 L.⁶

Protein binding

Both osilodrostat and its M34.5 metabolite are minimally protein-bound in plasma at less than 40%.^6,7 The extent of protein-binding is independent of drug concentration.⁷ The specific plasma proteins to which osilodrostat binds have not been elucidated.

Metabolism

Osilodrostat is extensively metabolized - approximately 80% of an orally administered dose is excreted as metabolites, and this is the predominant means of drug clearance.⁷ The most abundant metabolites in plasma are M35.4 (di-oxygenated osilodrostat), M16.5, and M24.9 at 51%, 9%, and 7% of the administered dose, respectively.⁷ The M34.5 and M24.9 metabolites have longer half-lives than the parent drug which may lead to accumulation with twice-daily dosing. Of the thirteen metabolites observed in the urine, the most abundant are M16.5 (osilodrostat glucuronide), M22 (a glucuronide conjugate of M34.5), and M24.9 at 17%, 13%, and 11% of the administered dose, respectively.⁷ The M34.5 metabolite accounts for less than 1% of the dose excreted in urine, but its glucuronide conjugate (M22) accounts for approximately 13%.⁷

The biotransformation of osilodrostat is mediated by multiple cytochrome P450 (CYP) and UDP-glucuronosyltransferase (UGT) enzymes, though no single enzyme appears to contribute >25% to the total clearance.⁶ Of the total clearance, approximately 26% is CYP-mediated, 19% is UGT-mediated, and 50% is mediated by other enzymes.⁷ The formation of M34.5, the major metabolite of osilodrostat, is likely non-CYP-mediated. The formation of osilodrostat glucuronide (M16.5), its major urinary metabolite, is catalyzed by UGT1A4, UGT2B7, and UGT2B10.⁷

In vitro data suggest that none of the metabolites contribute to the therapeutic efficacy of osilodrostat, but the M34.5 metabolite has been implicated in the inhibition and/or induction of multiple enzymes and transporters.^6,7

Route of elimination

Following oral administration of radiolabeled osilodrostat, 90.6% of the radioactivity was eliminated in the urine with only 1.58% in the feces.⁶ Only 5.2% of the administered dose was eliminated in the urine as unchanged parent drug, suggesting that metabolism followed by urinary elimination is osildrostat's primary means of clearance.⁶

Half-life

The elimination half-life of osilodrostat is approximately 4 hours.^6,4

Clearance

Data regarding the oral clearance of osilodrostat are not currently available.

Adverse Effects

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Toxicity

As an inhibitor of cortisol synthesis, overdose with osilodrostat may result in severe hypocortisolism.⁶ Symptoms may include nausea, vomiting, fatigue, hypotension, abdominal pain, loss of appetite, dizziness, and syncope. Treatment of overdose should include assessment of cortisol levels and supplementation with exogenous corticosteroids as necessary, as well as careful monitoring of the patient's heart rhythm, blood glucose, electrolytes, and blood pressure.⁶

Toxicity related to its osilodrostat's mechanism of action is difficult to observe in animal test subjects as human receptor profiles and densities for osilodrostat targets differ in humans as compared to these animals - for this reason, toxicological data gleaned from animal trials is of uncertain clinical relevance in humans.⁸

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.

• Approved
• Vet approved
• Nutraceutical
• Illicit
• Withdrawn
• Investigational
• Experimental
• All Drugs

Drug	Interaction
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Abametapir	The serum concentration of Osilodrostat can be increased when it is combined with Abametapir.
Abatacept	The metabolism of Osilodrostat can be increased when combined with Abatacept.
Abemaciclib	The metabolism of Abemaciclib can be decreased when combined with Osilodrostat.
Abrocitinib	The metabolism of Abrocitinib can be decreased when combined with Osilodrostat.
Acalabrutinib	The metabolism of Acalabrutinib can be decreased when combined with Osilodrostat.

Food Interactions

• Take with or without food. Administration with food slightly alters absorption, but not to a clinically significant extent.

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Product Ingredients

Ingredient	UNII	CAS	InChI Key
Osilodrostat phosphate	Y6581YAW9V	1315449-72-9	FMCPYRDGUZBOJZ-BTQNPOSSSA-N

Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End	Region	Image
Isturisa	Tablet, film coated	5 mg	Oral	Recordati Rare Diseases	2020-12-16	Not applicable
Isturisa	Tablet, coated	5 mg/1	Oral	RECORDATI RARE DISEASES, INC.	2020-03-31	Not applicable
Isturisa	Tablet, film coated	1 mg	Oral	Recordati Rare Diseases	2020-12-16	Not applicable
Isturisa	Tablet, coated	1 mg/1	Oral	RECORDATI RARE DISEASES, INC.	2020-03-31	Not applicable
Isturisa	Tablet, film coated	10 mg	Oral	Recordati Rare Diseases	2020-12-16	Not applicable

Categories

ATC Codes

H02CA02 — Osilodrostat

• H02CA — Anticorticosteroids
• H02C — ANTIADRENAL PREPARATIONS
• H02 — CORTICOSTEROIDS FOR SYSTEMIC USE
• H — SYSTEMIC HORMONAL PREPARATIONS, EXCL. SEX HORMONES AND INSULINS

Drug Categories

• Antiadrenal Preparations
• Anticorticosteroids
• Cortisol Synthesis Inhibitors
• Cytochrome P-450 CYP11B2, antagonists & inhibitors
• Cytochrome P-450 CYP1A2 Inhibitors
• Cytochrome P-450 CYP1A2 Inhibitors (moderate)
• Cytochrome P-450 CYP2B6 Substrates
• Cytochrome P-450 CYP2C19 Inhibitors
• Cytochrome P-450 CYP2C19 Inhibitors (weak)
• Cytochrome P-450 CYP2D6 Inhibitors
• Cytochrome P-450 CYP2D6 Inhibitors (weak)
• Cytochrome P-450 CYP2D6 Substrates
• Cytochrome P-450 CYP2E1 Inhibitors
• Cytochrome P-450 CYP2E1 Inhibitors (strength unknown)
• Cytochrome P-450 CYP3A Inhibitors
• Cytochrome P-450 CYP3A Substrates
• Cytochrome P-450 CYP3A4 Inhibitors
• Cytochrome P-450 CYP3A4 Inhibitors (weak)
• Cytochrome P-450 CYP3A4 Substrates
• Cytochrome P-450 CYP3A5 Inhibitors
• Cytochrome P-450 CYP3A5 Inhibitors (weak)
• Cytochrome P-450 Enzyme Inhibitors
• Cytochrome P-450 Substrates
• Cytochrome P450 11B1 Inhibitors
• MATE 1 Inhibitors
• MATE inhibitors
• OAT1/SLC22A6 inhibitors
• OAT3/SLC22A8 Inhibitors
• OATP1B1/SLCO1B1 Inhibitors
• OCT1 inhibitors
• OCT2 Inhibitors
• Systemic Hormonal Preparations, Excl. Sex Hormones and Insulins
• UGT1A4 substrates
• UGT2B7 substrates

Chemical TaxonomyProvided by Classyfire

Description

This compound belongs to the class of organic compounds known as benzonitriles. These are organic compounds containing a benzene bearing a nitrile substituent.

Kingdom

Organic compounds

Super Class

Benzenoids

Class

Benzene and substituted derivatives

Sub Class

Benzonitriles

Direct Parent

Benzonitriles

Alternative Parents

Fluorobenzenes / N-substituted imidazoles / Aryl fluorides / Heteroaromatic compounds / Nitriles / Azacyclic compounds / Organofluorides / Hydrocarbon derivatives

Substituents

Aromatic heteropolycyclic compound / Aryl fluoride / Aryl halide / Azacycle / Azole / Benzonitrile / Carbonitrile / Cyanide / Fluorobenzene / Halobenzene

Molecular Framework

Aromatic heteropolycyclic compounds

External Descriptors

Not Available

Affected organisms

• Humans and other mammals

Chemical Identifiers

UNII

5YL4IQ1078

CAS number

928134-65-0

InChI Key

USUZGMWDZDXMDG-CYBMUJFWSA-N

InChI

InChI=1S/C13H10FN3/c14-12-5-9(6-15)1-3-11(12)13-4-2-10-7-16-8-17(10)13/h1,3,5,7-8,13H,2,4H2/t13-/m1/s1

IUPAC Name

3-fluoro-4-[(5R)-5H,6H,7H-pyrrolo[1,2-c]imidazol-5-yl]benzonitrile

SMILES

FC1=C(C=CC(=C1)C#N)[C@H]1CCC2=CN=CN12

References

General References

1. Armani S, Ting L, Sauter N, Darstein C, Tripathi AP, Wang L, Zhu B, Gu H, Chun DY, Einolf HJ, Kulkarni S: Drug Interaction Potential of Osilodrostat (LCI699) Based on Its Effect on the Pharmacokinetics of Probe Drugs of Cytochrome P450 Enzymes in Healthy Adults. Clin Drug Investig. 2017 May;37(5):465-472. doi: 10.1007/s40261-017-0497-0. [Article]
2. Papillon JP, Adams CM, Hu QY, Lou C, Singh AK, Zhang C, Carvalho J, Rajan S, Amaral A, Beil ME, Fu F, Gangl E, Hu CW, Jeng AY, LaSala D, Liang G, Logman M, Maniara WM, Rigel DF, Smith SA, Ksander GM: Structure-Activity Relationships, Pharmacokinetics, and in Vivo Activity of CYP11B2 and CYP11B1 Inhibitors. J Med Chem. 2015 Jun 11;58(11):4749-70. doi: 10.1021/acs.jmedchem.5b00407. Epub 2015 May 21. [Article]
3. Weldon SM, Cerny MA, Gueneva-Boucheva K, Cogan D, Guo X, Moss N, Parmentier JH, Richman JR, Reinhart GA, Brown NF: Selectivity of BI 689648, a Novel, Highly Selective Aldosterone Synthase Inhibitor: Comparison with FAD286 and LCI699 in Nonhuman Primates. J Pharmacol Exp Ther. 2016 Oct;359(1):142-50. doi: 10.1124/jpet.116.236463. Epub 2016 Aug 1. [Article]
4. Duggan S: Osilodrostat: First Approval. Drugs. 2020 Mar 5. pii: 10.1007/s40265-020-01277-0. doi: 10.1007/s40265-020-01277-0. [Article]
5. Prague JK, May S, Whitelaw BC: Cushing's syndrome. BMJ. 2013 Mar 27;346:f945. doi: 10.1136/bmj.f945. [Article]
6. FDA Approved Drug Products: Isturisa (osilodrostat) oral tablets [Link]
7. EMA Summary of Product Characteristics: Isturisa (osilodrostat) oral tablets [Link]
8. EMA Assessment Report: Isturisa (osilodrostat) oral tablets [Link]
9. FDA News Release: Osilodrostat Approval [Link]

External Links

PubChem Compound

44139752

PubChem Substance

347828182

ChemSpider

29340911

BindingDB

50444549

RxNav

2286252

ChEMBL

CHEMBL3099695

ZINC

ZINC000072318114

PDBe Ligand

YSY

Wikipedia

Osilodrostat

PDB Entries

7m8v

FDA label

Download (456 KB)

Clinical Trials

Clinical Trials

Phase	Status	Purpose	Conditions	Count
3	Completed	Treatment	Cushing's Disease	2
2	Active Not Recruiting	Treatment	Cushing's Syndrome	1
2	Completed	Treatment	Adrenal Adenoma / AIMAH / Carcinoma Adrenal / Cushing's Syndrome / Ectopic Corticotropin Syndrome / PPNAD	1
2	Completed	Treatment	Cushing's Disease	1
2	Completed	Treatment	Hypertension	2

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Tablet, coated	Oral	1 mg/1
Tablet, coated	Oral	10 mg/1
Tablet, coated	Oral	5 mg/1
Tablet, film coated	Oral	1 MG
Tablet, film coated	Oral	10 MG
Tablet, film coated	Oral	5 MG

Prices

Not Available

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)	Region
US8609862	No	2013-12-17	2031-01-13
US8835646	No	2014-09-16	2026-08-23
US8314097	No	2012-11-20	2029-03-27
US10143680	No	2018-12-04	2035-07-06
US9434754	No	2016-09-06	2031-01-13
US10709691	No	2020-07-14	2035-10-12

Properties

State

Solid

Experimental Properties

Not Available

Predicted Properties

Property	Value	Source
Water Solubility	0.356 mg/mL	ALOGPS
logP	2.18	ALOGPS
logP	2.11	Chemaxon
logS	-2.8	ALOGPS
pKa (Strongest Basic)	7.15	Chemaxon
Physiological Charge	1	Chemaxon
Hydrogen Acceptor Count	2	Chemaxon
Hydrogen Donor Count	0	Chemaxon
Polar Surface Area	41.61 Å2	Chemaxon
Rotatable Bond Count	1	Chemaxon
Refractivity	62.07 m3·mol-1	Chemaxon
Polarizability	22.53 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	No	Chemaxon

Predicted ADMET Features

Not Available

Spectra

Mass Spec (NIST)

Not Available

Spectra

Spectrum	Spectrum Type	Splash Key
Predicted GC-MS Spectrum - GC-MS	Predicted GC-MS	splash10-0f8a-3950000000-4431758f2deeb32e5959
Predicted MS/MS Spectrum - 10V, Positive (Annotated)	Predicted LC-MS/MS	splash10-004i-0290000000-fdefd08476f428b8aa9b
Predicted MS/MS Spectrum - 10V, Negative (Annotated)	Predicted LC-MS/MS	splash10-004i-0390000000-1d006989b149d7fecaf8
Predicted MS/MS Spectrum - 20V, Negative (Annotated)	Predicted LC-MS/MS	splash10-0a6r-0790000000-ae502d10f6141c5b9244
Predicted MS/MS Spectrum - 20V, Positive (Annotated)	Predicted LC-MS/MS	splash10-004i-0090000000-4039e092691e674e3f34
Predicted MS/MS Spectrum - 40V, Positive (Annotated)	Predicted LC-MS/MS	splash10-001i-2910000000-22ee732e9a23233da28d
Predicted MS/MS Spectrum - 40V, Negative (Annotated)	Predicted LC-MS/MS	splash10-0a59-2930000000-7590b4dc22c00dbb40de
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]-	150.64629	predicted	DeepCCS 1.0 (2019)
[M+H]+	153.04187	predicted	DeepCCS 1.0 (2019)
[M+Na]+	159.08003	predicted	DeepCCS 1.0 (2019)

Targets

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Details1. Cytochrome P450 11B1, mitochondrial

Kind

Protein

Organism

Humans

Pharmacological action

Yes

Actions

Inhibitor

General Function

Steroid 11-beta-monooxygenase activity

Specific Function

Has steroid 11-beta-hydroxylase activity. In addition to this activity, the 18 or 19-hydroxylation of steroids and the aromatization of androstendione to estrone have also been ascribed to cytochro...

Gene Name

CYP11B1

Uniprot ID

P15538

Uniprot Name

Cytochrome P450 11B1, mitochondrial

Molecular Weight

57572.44 Da

References

1. FDA Approved Drug Products: Isturisa (osilodrostat) oral tablets [Link]

Details2. Cytochrome P450 11B2, mitochondrial

Kind

Protein

Organism

Humans

Pharmacological action

No

Actions

Inhibitor

General Function

Steroid 11-beta-monooxygenase activity

Specific Function

Preferentially catalyzes the conversion of 11-deoxycorticosterone to aldosterone via corticosterone and 18-hydroxycorticosterone.

Gene Name

CYP11B2

Uniprot ID

P19099

Uniprot Name

Cytochrome P450 11B2, mitochondrial

Molecular Weight

57559.62 Da

References

1. Weldon SM, Cerny MA, Gueneva-Boucheva K, Cogan D, Guo X, Moss N, Parmentier JH, Richman JR, Reinhart GA, Brown NF: Selectivity of BI 689648, a Novel, Highly Selective Aldosterone Synthase Inhibitor: Comparison with FAD286 and LCI699 in Nonhuman Primates. J Pharmacol Exp Ther. 2016 Oct;359(1):142-50. doi: 10.1124/jpet.116.236463. Epub 2016 Aug 1. [Article]

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Drug created at October 20, 2016 20:52 / Updated at December 01, 2022 11:27