Identification

Name
Ivosidenib
Accession Number
DB14568
Type
Small Molecule
Groups
Approved, Investigational
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.

Structure
Thumb
Synonyms
Not Available
External IDs
AG-120
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
TibsovoTablet, film coated250 mg/1OralAgios Pharmaceuticals, Inc.2018-07-20Not applicableUs
Categories
UNII
Q2PCN8MAM6
CAS number
1448347-49-6
Weight
Average: 582.97
Monoisotopic: 582.1394008
Chemical Formula
C28H22ClF3N6O3
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

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
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]. Ivosidenib has not been observed to inhibit any form of IDH2 at micromolar concentrations.

TargetActionsOrganism
AIsocitrate dehydrogenase [NADP] cytoplasmic
inhibitor
Human
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

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
DrugInteraction
AcebutololThe serum concentration of Acebutolol can be increased when it is combined with Ivosidenib.
AcetaminophenThe serum concentration of Ivosidenib can be increased when it is combined with Acetaminophen.
Acetylsalicylic acidThe serum concentration of Acetylsalicylic acid can be increased when it is combined with Ivosidenib.
AlclometasoneThe metabolism of Alclometasone can be increased when combined with Ivosidenib.
AlfuzosinThe risk or severity of QTc prolongation can be increased when Alfuzosin is combined with Ivosidenib.
AlimemazineThe risk or severity of QTc prolongation can be increased when Alimemazine is combined with Ivosidenib.
AmcinonideThe metabolism of Amcinonide can be increased when combined with Ivosidenib.
AmiodaroneThe risk or severity of QTc prolongation can be increased when Ivosidenib is combined with Amiodarone.
AmitriptylineThe serum concentration of Amitriptyline can be increased when it is combined with Ivosidenib.
AmlodipineThe serum concentration of Ivosidenib can be increased when it is combined with Amlodipine.
Food Interactions
Not Available

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]
External Links
ChemSpider
38772333
ChEMBL
CHEMBL3989958
Wikipedia
Ivosidenib
FDA label
Download (460 KB)
MSDS
Download (56.5 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1Active Not RecruitingTreatmentCholangiocarcinomas / Chondrosarcomas / Gliomas / Other Advanced Solid Tumors1
1Active Not RecruitingTreatmentOther IDH1-mutated Positive Hematologic Malignancies / Relapsed or Refractory Acute Myeloid Leukemia (AML) / Untreated AML1
1CompletedTreatmentHealthy Volunteers1
1CompletedTreatmentHepatic Impairment1
1Not Yet RecruitingTreatmentIDH1 Mutation Myeloid Neoplasms1
1RecruitingTreatmentAML 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
1RecruitingTreatmentGliomas1
1, 2RecruitingTreatmentAdvanced Hematologic Malignancies / Leukemia Acute Myeloid Leukemia (AML) / Other Diseases of Blood and Blood-Forming Organs1
1, 2RecruitingTreatmentLeukemia Acute Myeloid Leukemia (AML)1
1, 2RecruitingTreatmentPreviously Untreated Acute Myeloid Leukemia1
2Not Yet RecruitingTreatmentLeukemia Acute Myeloid Leukemia (AML) / Myelodysplastic Syndromes1
3RecruitingTreatmentAdvanced Cholangiocarcinoma / Metastatic Cholangiocarcinoma1
Not AvailableApproved for MarketingNot AvailableLeukemia Acute Myeloid Leukemia (AML) / Relapsed Adult AML / Relapsed Pediatric AML1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Tablet, film coatedOral250 mg/1
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US9474779No2013-08-192033-08-19Us
US9850277No2013-01-182033-01-18Us
US9968595No2015-03-132035-03-13Us

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

Taxonomy

Classification
Not classified

Targets

Kind
Protein
Organism
Human
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
Human
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
Human
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
Kind
Protein
Organism
Human
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
CYP2C9
Uniprot ID
P11712
Uniprot Name
Cytochrome P450 2C9
Molecular Weight
55627.365 Da
Kind
Protein
Organism
Human
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
Human
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
Human
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 September 17, 2018 21:07