Identification

Name
Ivosidenib
Accession Number
DB14568
Description

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
Thumb
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.

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

TargetActionsOrganism
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
Learn about our commercial Adverse Effects data.
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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.

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 Ivosidenib can be increased when it is combined with Abametapir.
AbataceptThe metabolism of Ivosidenib can be increased when combined with Abatacept.
AbirateroneThe metabolism of Abiraterone can be increased when combined with Ivosidenib.
AcalabrutinibThe metabolism of Acalabrutinib can be increased when combined with Ivosidenib.
AcebutololThe risk or severity of QTc prolongation can be increased when Acebutolol is combined with Ivosidenib.
AcenocoumarolThe metabolism of Acenocoumarol can be increased when combined with Ivosidenib.
AcetaminophenThe metabolism of Ivosidenib can be increased when combined with Acetaminophen.
AcetazolamideThe metabolism of Ivosidenib can be decreased when combined with Acetazolamide.
AcrivastineThe risk or severity of QTc prolongation can be increased when Acrivastine is combined with Ivosidenib.
AcyclovirThe excretion of Acyclovir can be decreased when combined with Ivosidenib.
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
  • 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

Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
TibsovoTablet, film coated250 mg/1OralAgios Pharmaceuticals, Inc.2018-07-20Not applicableUS 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
L01XX62 — Ivosidenib
Drug Categories
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

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][[email protected]@](N(C(=O)[[email protected]]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. [PubMed:27621679]
  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. [PubMed:28375741]
  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. [PubMed:26700815]
  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. [PubMed:21130701]
  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. [PubMed:29670690]
  6. FDA Press Release Ivosidenib Approval [Link]
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
PhaseStatusPurposeConditionsCount
3Active Not RecruitingTreatmentAdvanced Cholangiocarcinoma / Metastatic Cholangiocarcinoma1
3RecruitingTreatmentAcute Myeloid Leukemia (AML) / AML Arising From Myelodysplastic Syndrome (MDS) / Newly Diagnosed Acute Myeloid Leukemia (AML) / Untreated AML1
3RecruitingTreatmentAcute Myeloid Leukemia (AML) / Myelodysplastic Syndrome With Excess Blasts-21
2Not Yet RecruitingTreatmentAcute Myeloid Leukemia With Gene Mutations / Acute, recurrent Myeloid Leukemia / Myelodysplastic Syndrome / Myeloproliferative Neoplasms / Refractory Acute Myelogenous Leukemia (AML)1
2Not Yet RecruitingTreatmentAdvanced Solid Tumors / Gliomas / IDH1 Mutation1
2RecruitingTreatmentAcute Myeloid Leukemia (AML) / Myelodysplastic Syndromes (MDS)1
2RecruitingTreatmentChondrosarcoma, Grade 2 / Chondrosarcoma, Grade 3 / Chondrosarcomas / IDH1 Gene Mutation1
2RecruitingTreatmentEpendymoma, Recurrent / Recurrent Ewing 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 Sarcoma / Refractory WHO Grade II Glioma / Wilms' tumor1
2SuspendedTreatmentAcute Myeloid Leukemia (AML) / Myelodysplastic Syndromes (MDS)1
1Active Not RecruitingTreatmentAML Arising After Exposure to Genotoxic Injury / AML Arising From Antecedent Hematologic Disorder (AHD) / AML Arising From Myelodysplastic Syndrome (MDS) / Newly Diagnosed Acute Myeloid Leukemia (AML) / Untreated AML1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Tablet, film coatedOral250 mg/1
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US9474779No2016-10-252033-08-19US flag
US9850277No2017-12-262033-01-18US flag
US9968595No2018-05-152035-03-13US flag
US10449184No2019-10-222035-03-13US flag
US10610125No2010-06-212030-06-21US 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 Solubility0.0208 mg/mLALOGPS
logP2.52ALOGPS
logP3.01ChemAxon
logS-4.4ALOGPS
pKa (Strongest Acidic)12.14ChemAxon
pKa (Strongest Basic)1.81ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count6ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area119.29 Å2ChemAxon
Rotatable Bond Count7ChemAxon
Refractivity139.33 m3·mol-1ChemAxon
Polarizability53.42 Å3ChemAxon
Number of Rings5ChemAxon
Bioavailability1ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
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

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Inducer
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
  1. 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
  1. 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
  1. 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
Substrate
Inhibitor
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 on July 20, 2018 10:42 / Updated on July 07, 2020 16:27

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