Ivosidenib

Identification

Summary

Ivosidenib is an isocitrate dehydrogenase-1 inhibitor used to treat acute myeloid leukemia with a susceptible mutation.

Brand Names

Tibsovo

Generic Name

Ivosidenib

DrugBank Accession Number

DB14568

Background

Ivosidenib is a first in class isocitrate dehydrogenase-1 (IDH1) approved for use by the FDA in acute myeloid leukemia (AML) in July 2018 ⁶. Ivosidenib is now available in the United States under the trade name Tibsovo marketed by Agios Pharmaceuticals, Inc. Ivosidenib has been granted fast track, priority review, and orphan drug designations by the FDA.

This approval came alongside the approval for the RealTime IDH1 Assay which is meant as a companion diagnostic tool to detect IDH1 mutations ⁶. RealTime IDH1 Assay is marketed by Abbott Laboratories.

Type

Small Molecule

Groups

Approved, Investigational

Structure

3D

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MOLSDF3D-SDFPDBSMILESInChI

Similar Structures

Structure for Ivosidenib (DB14568)

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Weight

Average: 582.97
Monoisotopic: 582.1394008

Chemical Formula

C₂₈H₂₂ClF₃N₆O₃

Synonyms

• Ivosidenib

External IDs

• AG-120

Pharmacology

Indication

Ivosidenib is approved for use in the treatment of relapsed or refractory AML with a susceptible IDH1 mutation as detected by an FDA-approved test ^Label.

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Associated Conditions

• Refractory, relapsed Acute Myeloid Leukemia

Contraindications & Blackbox Warnings

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Pharmacodynamics

Many cancers undergo missense mutations of their IDH1 gene leading to substitution of arginine 132 residue of the IDH1 enzyme ^1,2. Furthermore, methylation sensitive insulators can no longer regulate the activation of oncogenes when histones are hypermethylated ³. In AML this hypermethylation is known to disrupt hematopoietic differentiation ⁴.

Ivosidenib reduces the production of D-2HG, relieving the inhibition of histone demethylases and restoring normal methylation conditions ⁵. This restores cell differentiation and oncogene regulation leading to regression of the cancer.

Mechanism of action

Ivosidenib is a reversible inhibitor of IDH1 which is non-competitive with respect to the cofactor NADH. It binds to many different 132-substituted IDH1 mutants as well as the wild type enzyme. It is considered to be a slow-binder of the wild type enzyme and binds to mutant enzymes at lower concentrations, both of which may contribute its selectivity ^5,Label. Ivosidenib has not been observed to inhibit any form of IDH2 at micromolar concentrations.

Target	Actions	Organism
AIsocitrate dehydrogenase [NADP] cytoplasmic	inhibitor	Humans

Absorption

Ivosidenib has a Tmax of 3 hours following oral administration of a 2 250 mg tablets (total 500 mg) ^Label. When given with a high-fat meal, Cmax increases by 98% and AUC by 25%.

The AUC and Cmax increase in a less than dose-proportional manner in the range of 200-1200 mg daily ^Label. Accumulation ratios have been determined to be 1.9 for AUC and 1.5 for Cmax over the course of one month. Steady state is known to be reached within 14 days of daily administration.

Volume of distribution

Ivosidenib has a mean apparent Vd of 234 L at steady-state ^Label.

Protein binding

Ivosidenib is 92-96% bound to plasma proteins as determined in vitro ^Label.

Metabolism

Over 92% of Ivosidenib is present in circulation as the parent drug ^Label. Metabolism occurs primarily through CYP3A4 with some contribution from N-dealkylation and hydrolysis.

Route of elimination

Following oral administration, 77% of Ivosidenib is eliminated in the feces with 67% present as the parent drug ^Label. 17% is excreted in the urine with 10% as the parent drug.

No clinically meaningful effects on elimination have been observed with mild to moderate renal impairment or mild hepatic impairment ^Label. Changes in patients with severe renal impairment or moderate too severe hepatic impairment have not been investigated.

Half-life

Ivosidenib has a terminal half-life of 93 h ^Label.

Clearance

Ivosidenib has an apparent clearance rate of 4.3 L/h

Adverse Effects

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Toxicity

Ivosidenib does not appear to be mutagenic or clastogenic ^Label. In rats, uterine atrophy was noted as non-tolerated dose levels in a 90 day repeat dose test with twice daily adiminstration. Carcinogenicity has not been assessed.

Animal embryo-fetal tests suggest Ivosidenib may cause fetal harm in pregnant patients ^Label. When administered to pregnant rabbits, embryo-fetal mortality and growth changes occurred starting doses equivalent to 2 times normal recommended human exposure.

Ivosidenib is associated with development of differentiation syndrome presenting as noninfectious leukocytosis ^Label, peripheral edema, pyrexia, dyspnea, pleural effusion, hypotension, hypoxia, pulmonary edema, pneumonitis, pericardial effusion, rash, fluid overload, tumor lysis syndrome, and increased serum creatinine. 19% of patients in a clinical trial experienced this.

Ivosidenib is also associated with QTc prolongation ^Label. 9% of patients in a clinical trial were found to have a QTc interval greater than 500 msec and 14% had an increase from baseline greater than 60 msec.

Gullain-Barre syndrome is a rare but severe condition associated with Ivosidenib use ^Label. <1% of patients in a clinical trial experienced this, presenting as motor and/or sensory neuropathy such as unilateral or bilateral weakness, sensory alterations, paresthesias, or difficulty breathing.

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 Ivosidenib can be increased when it is combined with Abametapir.
Abatacept	The metabolism of Ivosidenib can be increased when combined with Abatacept.
Abemaciclib	The serum concentration of Abemaciclib can be increased when it is combined with Ivosidenib.
Abiraterone	The metabolism of Ivosidenib can be decreased when combined with Abiraterone.
Acalabrutinib	The metabolism of Acalabrutinib can be increased when combined with Ivosidenib.
Acamprosate	The excretion of Acamprosate can be decreased when combined with Ivosidenib.
Acenocoumarol	The metabolism of Acenocoumarol can be increased when combined with Ivosidenib.
Acetaminophen	The metabolism of Ivosidenib can be increased when combined with Acetaminophen.
Acetazolamide	The metabolism of Ivosidenib can be decreased when combined with Acetazolamide.
Acrivastine	The risk or severity of QTc prolongation can be increased when Acrivastine is combined with Ivosidenib.

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Food Interactions

• Do not take with or immediately after a high-fat meal. Administration of ivosidenib with a high-fat meal increases the Cmax and AUC of ivosidenib by 98 and 25%, respectively.
• Exercise caution with grapefruit products. Grapefruit inhibits CYP3A metabolism, which may increase the serum concentration of ivosidenib. Dose adjustment may be necessary if co-administered.
• Exercise caution with St. John's Wort. This herb induces CYP3A metabolism and may reduce serum levels of ivosidenib.
• Take at the same time every day.
• Take with or without food.

Products

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Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End	Region	Image
Tibsovo	Tablet, film coated	250 mg/1	Oral	Agios Pharmaceuticals, Inc.	2018-07-20	Not applicable

Categories

ATC Codes

L01XX62 — Ivosidenib

• L01XX — Other antineoplastic agents
• L01X — OTHER ANTINEOPLASTIC AGENTS
• L01 — ANTINEOPLASTIC AGENTS
• L — ANTINEOPLASTIC AND IMMUNOMODULATING AGENTS

Drug Categories

• Amino Acids
• Amino Acids, Peptides, and Proteins
• Antineoplastic Agents
• Antineoplastic and Immunomodulating Agents
• Cytochrome P-450 CYP2B6 Inducers
• Cytochrome P-450 CYP2B6 Inducers (strength unknown)
• Cytochrome P-450 CYP2C8 Inducers
• Cytochrome P-450 CYP2C8 Inducers (strength unknown)
• Cytochrome P-450 CYP2C9 Inducers
• Cytochrome P-450 CYP2C9 Inducers (strength unknown)
• Cytochrome P-450 CYP3A Inducers
• Cytochrome P-450 CYP3A Substrates
• Cytochrome P-450 CYP3A4 Inducers
• Cytochrome P-450 CYP3A4 Inducers (strength unknown)
• Cytochrome P-450 CYP3A4 Substrates
• Cytochrome P-450 CYP3A4 Substrates with a Narrow Therapeutic Index
• Cytochrome P-450 Enzyme Inducers
• Cytochrome P-450 Substrates
• Enzyme Inhibitors
• Moderate Risk QTc-Prolonging Agents
• Narrow Therapeutic Index Drugs
• OAT3/SLC22A8 Inhibitors
• P-glycoprotein inhibitors
• P-glycoprotein substrates
• P-glycoprotein substrates with a Narrow Therapeutic Index
• QTc Prolonging Agents

Chemical TaxonomyProvided by Classyfire

Description

This compound belongs to the class of organic compounds known as proline and derivatives. These are compounds containing proline or a derivative thereof resulting from reaction of proline at the amino group or the carboxy group, or from the replacement of any hydrogen of glycine by a heteroatom.

Kingdom

Organic compounds

Super Class

Organic acids and derivatives

Class

Carboxylic acids and derivatives

Sub Class

Amino acids, peptides, and analogues

Direct Parent

Proline and derivatives

Alternative Parents

Alpha amino acid amides / Phenylacetamides / Pyrrolidinecarboxamides / Chlorobenzenes / Pyrrolidine-2-ones / Pyridines and derivatives / Aryl chlorides / Aryl fluorides / Imidolactams / Tertiary carboxylic acid amides / Heteroaromatic compounds / Secondary carboxylic acid amides / Lactams / Nitriles / Azacyclic compounds / Organic oxides / Carbonyl compounds / Organochlorides / Organofluorides / Hydrocarbon derivatives / Alkyl fluorides

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Substituents

2-pyrrolidone / Alkyl fluoride / Alkyl halide / Alpha-amino acid amide / Aromatic heteromonocyclic compound / Aryl chloride / Aryl fluoride / Aryl halide / Azacycle / Benzenoid / Carbonitrile / Carbonyl group / Carboxamide group / Chlorobenzene / Cyanide / Halobenzene / Heteroaromatic compound / Hydrocarbon derivative / Imidolactam / Lactam / Monocyclic benzene moiety / Nitrile / Organic nitrogen compound / Organic oxide / Organic oxygen compound / Organochloride / Organofluoride / Organohalogen compound / Organoheterocyclic compound / Organonitrogen compound / Organooxygen compound / Phenylacetamide / Proline or derivatives / Pyridine / Pyrrolidine / Pyrrolidine carboxylic acid or derivatives / Pyrrolidine-2-carboxamide / Pyrrolidone / Secondary carboxylic acid amide / Tertiary carboxylic acid amide

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Molecular Framework

Aromatic heteromonocyclic compounds

External Descriptors

Not Available

Affected organisms

Not Available

Chemical Identifiers

UNII

Q2PCN8MAM6

CAS number

1448347-49-6

InChI Key

WIJZXSAJMHAVGX-DHLKQENFSA-N

InChI

InChI=1S/C28H22ClF3N6O3/c29-21-4-2-1-3-20(21)25(26(40)36-18-11-28(31,32)12-18)37(19-10-17(30)14-34-15-19)27(41)22-5-6-24(39)38(22)23-9-16(13-33)7-8-35-23/h1-4,7-10,14-15,18,22,25H,5-6,11-12H2,(H,36,40)/t22-,25-/m0/s1

IUPAC Name

(2S)-2-(2-chlorophenyl)-2-{1-[(2S)-1-(4-cyanopyridin-2-yl)-5-oxopyrrolidin-2-yl]-N-(5-fluoropyridin-3-yl)formamido}-N-(3,3-difluorocyclobutyl)acetamide

SMILES

[H][C@@](N(C(=O)[C@]1([H])CCC(=O)N1C1=NC=CC(=C1)C#N)C1=CC(F)=CN=C1)(C(=O)NC1CC(F)(F)C1)C1=C(Cl)C=CC=C1

References

General References

1. Mondesir J, Willekens C, Touat M, de Botton S: IDH1 and IDH2 mutations as novel therapeutic targets: current perspectives. J Blood Med. 2016 Sep 2;7:171-80. doi: 10.2147/JBM.S70716. eCollection 2016. [Article]
2. Dang L, Su SM: Isocitrate Dehydrogenase Mutation and (R)-2-Hydroxyglutarate: From Basic Discovery to Therapeutics Development. Annu Rev Biochem. 2017 Jun 20;86:305-331. doi: 10.1146/annurev-biochem-061516-044732. Epub 2017 Apr 3. [Article]
3. Flavahan WA, Drier Y, Liau BB, Gillespie SM, Venteicher AS, Stemmer-Rachamimov AO, Suva ML, Bernstein BE: Insulator dysfunction and oncogene activation in IDH mutant gliomas. Nature. 2016 Jan 7;529(7584):110-4. doi: 10.1038/nature16490. Epub 2015 Dec 23. [Article]
4. Figueroa ME, Abdel-Wahab O, Lu C, Ward PS, Patel J, Shih A, Li Y, Bhagwat N, Vasanthakumar A, Fernandez HF, Tallman MS, Sun Z, Wolniak K, Peeters JK, Liu W, Choe SE, Fantin VR, Paietta E, Lowenberg B, Licht JD, Godley LA, Delwel R, Valk PJ, Thompson CB, Levine RL, Melnick A: Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell. 2010 Dec 14;18(6):553-67. doi: 10.1016/j.ccr.2010.11.015. Epub 2010 Dec 9. [Article]
5. Popovici-Muller J, Lemieux RM, Artin E, Saunders JO, Salituro FG, Travins J, Cianchetta G, Cai Z, Zhou D, Cui D, Chen P, Straley K, Tobin E, Wang F, David MD, Penard-Lacronique V, Quivoron C, Saada V, de Botton S, Gross S, Dang L, Yang H, Utley L, Chen Y, Kim H, Jin S, Gu Z, Yao G, Luo Z, Lv X, Fang C, Yan L, Olaharski A, Silverman L, Biller S, Su SM, Yen K: Discovery of AG-120 (Ivosidenib): A First-in-Class Mutant IDH1 Inhibitor for the Treatment of IDH1 Mutant Cancers. ACS Med Chem Lett. 2018 Jan 19;9(4):300-305. doi: 10.1021/acsmedchemlett.7b00421. eCollection 2018 Apr 12. [Article]
6. FDA Press Release Ivosidenib Approval [Link]

External Links

ChemSpider

38772333

RxNav

2049873

ChEBI

145430

ChEMBL

CHEMBL3989958

ZINC

ZINC000205136523

Wikipedia

Ivosidenib

FDA label

Download (460 KB)

MSDS

Download (56.5 KB)

Clinical Trials

Clinical Trials

Phase	Status	Purpose	Conditions	Count
3	Active Not Recruiting	Treatment	Acute Myeloid Leukemia (AML) / AML Arising From Myelodysplastic Syndrome (MDS) / Newly Diagnosed Acute Myeloid Leukemia (AML) / Untreated AML	1
3	Completed	Treatment	Cholangiocarcinoma Advanced / Metastatic Cholangiocarcinoma	1
3	Recruiting	Treatment	Acute Myeloid Leukemia (AML) / Myelodysplastic Syndrome With Excess Blasts-2	1
2	Not Yet Recruiting	Treatment	Clonal Cytopenia of Undetermined Significance	1
2	Recruiting	Treatment	Acute Myeloid Leukemia (AML) / Myelodysplastic Syndromes (MDS)	1
2	Recruiting	Treatment	Acute Myeloid Leukemia With Gene Mutations / Acute, recurrent Myeloid Leukemia / Myelodysplastic Syndromes (MDS) / Myeloproliferative Neoplasms (MPNs) / Refractory Acute Myelogenous Leukemia (AML)	1
2	Recruiting	Treatment	Cancer of Unknown Primary Site	1
2	Recruiting	Treatment	Chondrosarcoma, Grade 2 / Chondrosarcoma, Grade 3 / Chondrosarcomas / IDH1 Gene Mutation	1
2	Recruiting	Treatment	Ependymoma, Recurrent / Recurrent Ewing's Sarcoma / Recurrent Hepatoblastoma / Recurrent Langerhans Cell Histiocytosis / Recurrent Malignant Germ Cell Tumor / Recurrent Malignant Gliomas / Recurrent Malignant Solid Neoplasm / Recurrent Medulloblastoma / Recurrent Neuroblastoma / Recurrent Non-Hodgkin Lymphoma / Recurrent Osteosarcoma / Recurrent Peripheral Primitive Neuroectodermal Tumor / Recurrent Rhabdoid Tumor / Recurrent Rhabdomyosarcoma / Recurrent Soft Tissue Sarcoma / Recurrent WHO Grade II Glioma / Refractory Ependymoma / Refractory Ewing Sarcoma / Refractory Hepatoblastoma / Refractory Langerhans cell histiocytosis / Refractory Malignant Germ Cell Tumor / Refractory Malignant Glioma / Refractory Malignant Solid Neoplasm / Refractory Medulloblastoma / Refractory Neuroblastoma / Refractory Non-Hodgkin's lymphoma / Refractory Osteosarcoma / Refractory Peripheral Primitive Neuroectodermal Tumor / Refractory Rhabdoid Tumor / Refractory Rhabdomyosarcoma / Refractory Soft Tissue Sarcomas / Refractory WHO Grade II Glioma / Wilms' tumor	1
2	Recruiting	Treatment	Gliomas / IDH1 Mutation / Solid Tumors, Advanced Solid Tumors	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Tablet, film coated	Oral	250 mg/1

Prices

Not Available

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)	Region
US9474779	No	2016-10-25	2033-08-19
US9850277	No	2017-12-26	2033-01-18
US9968595	No	2018-05-15	2035-03-13
US10449184	No	2019-10-22	2035-03-13
US10610125	No	2020-04-07	2030-06-21
US10799490	No	2020-10-13	2035-03-13
US10980788	No	2019-06-07	2039-06-07

Properties

State

Solid

Experimental Properties

Not Available

Predicted Properties

Property	Value	Source
Water Solubility	0.0208 mg/mL	ALOGPS
logP	2.52	ALOGPS
logP	3.01	ChemAxon
logS	-4.4	ALOGPS
pKa (Strongest Acidic)	12.14	ChemAxon
pKa (Strongest Basic)	1.81	ChemAxon
Physiological Charge	0	ChemAxon
Hydrogen Acceptor Count	6	ChemAxon
Hydrogen Donor Count	1	ChemAxon
Polar Surface Area	119.29 Å2	ChemAxon
Rotatable Bond Count	7	ChemAxon
Refractivity	139.33 m3·mol-1	ChemAxon
Polarizability	53.42 Å3	ChemAxon
Number of Rings	5	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

Not Available

Targets

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Details1. Isocitrate dehydrogenase [NADP] cytoplasmic

Kind

Protein

Organism

Humans

Pharmacological action

Yes

Actions

Inhibitor

General Function

Receptor binding

Specific Function

Not Available

Gene Name

IDH1

Uniprot ID

O75874

Uniprot Name

Isocitrate dehydrogenase [NADP] cytoplasmic

Molecular Weight

46659.005 Da

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Drug created on July 20, 2018 16:42 / Updated on February 21, 2021 18:54