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
- Weight
- Average: 582.97
Monoisotopic: 582.1394008 - Chemical Formula
- C28H22ClF3N6O3
- Synonyms
- Ivosidenib
- External IDs
- AG-120
Pharmacology
- Indication
Ivosidenib is indicated for the treatment of adult patients with a susceptible IDH1 mutation, as detected by an FDA-approved test, who have newly diagnosed acute myeloid leukemia (AML) and who are either 75 years of age or older or have comorbidities that preclude the use of intensive induction chemotherapy, who have relapsed or refractory AML, or who have locally advanced or metastatic cholangiocarcinoma and have previously received treatment.7
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- 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 inhibitorHumans - 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.
Drug Interaction Integrate drug-drug
interactions in your softwareAbametapir 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. Abrocitinib The serum concentration of Ivosidenib can be increased when it is combined with Abrocitinib. 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. Identify potential medication risksEasily compare up to 40 drugs with our drug interaction checker.Get severity rating, description, and management advice.Learn more - 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
- 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.
- Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Tibsovo Tablet, film coated 250 mg/1 Oral Servier Pharmaceutical LLC 2021-10-19 Not applicable US Tibsovo Tablet, film coated 250 mg/1 Oral Agios Pharmaceuticals, Inc. 2018-07-20 Not applicable US
Categories
- ATC Codes
- L01XX62 — Ivosidenib
- 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 show 11 more
- Substituents
- 2-pyrrolidone / Alkyl fluoride / Alkyl halide / Alpha-amino acid amide / Aromatic heteromonocyclic compound / Aryl chloride / Aryl fluoride / Aryl halide / Azacycle / Benzenoid show 30 more
- 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
- 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]
- 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]
- 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]
- 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]
- 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]
- FDA Press Release Ivosidenib Approval [Link]
- FDA Approved Drug Products: TIBSOVO (ivosidenib) tablets [Link]
- External Links
- ChemSpider
- 38772333
- BindingDB
- 363689
- 2049873
- ChEBI
- 145430
- ChEMBL
- CHEMBL3989958
- ZINC
- ZINC000205136523
- Wikipedia
- Ivosidenib
- FDA label
- Download (460 KB)
- MSDS
- Download (56.5 KB)
Clinical Trials
- Clinical Trials
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 US US9850277 No 2017-12-26 2033-01-18 US US9968595 No 2018-05-15 2035-03-13 US US10449184 No 2019-10-22 2035-03-13 US US10610125 No 2020-04-07 2030-06-21 US US10799490 No 2020-10-13 2035-03-13 US US10980788 No 2021-04-20 2039-06-07 US US10717764 No 2013-01-18 2033-01-18 US
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

- 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
References
- Megias-Vericat JE, Ballesta-Lopez O, Barragan E, Montesinos P: IDH1-mutated relapsed or refractory AML: current challenges and future prospects. Blood Lymphat Cancer. 2019 Jun 27;9:19-32. doi: 10.2147/BLCTT.S177913. eCollection 2019. [Article]
Enzymes
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- SubstrateInducer
- 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
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inducer
- General Function
- Steroid 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 oxidizes a variety of structurally un...
- Gene Name
- CYP2B6
- Uniprot ID
- P20813
- Uniprot Name
- Cytochrome P450 2B6
- Molecular Weight
- 56277.81 Da
References
- Ivosidenib FDA Label [File]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inducer
- Curator comments
- There are limited data in the literature supporting this enzyme action, however the FDA label states that ivosidenib may induce CYP2C9.
- General Function
- Steroid 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 oxidizes a variety of structurally un...
- Gene Name
- CYP2C9
- Uniprot ID
- P11712
- Uniprot Name
- Cytochrome P450 2C9
- Molecular Weight
- 55627.365 Da
References
- Ivosidenib FDA label [File]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inducer
- General Function
- Steroid 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 oxidizes a variety of structurally un...
- Gene Name
- CYP2C8
- Uniprot ID
- P10632
- Uniprot Name
- Cytochrome P450 2C8
- Molecular Weight
- 55824.275 Da
References
- Ivosidenib FDA Label [File]
Transporters
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inhibitor
- General Function
- Sodium-independent organic anion transmembrane transporter activity
- Specific Function
- Plays an important role in the excretion/detoxification of endogenous and exogenous organic anions, especially from the brain and kidney. Involved in the transport basolateral of steviol, fexofenad...
- Gene Name
- SLC22A8
- Uniprot ID
- Q8TCC7
- Uniprot Name
- Solute carrier family 22 member 8
- Molecular Weight
- 59855.585 Da
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- SubstrateInhibitor
- General Function
- Xenobiotic-transporting atpase activity
- Specific Function
- Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
- Gene Name
- ABCB1
- Uniprot ID
- P08183
- Uniprot Name
- Multidrug resistance protein 1
- Molecular Weight
- 141477.255 Da
Drug created at July 20, 2018 16:42 / Updated at March 10, 2022 09:37