IVOSIDENIB

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C28H22ClF3N6O3
Molecular Weight	582.961
Optical Activity	UNSPECIFIED
Defined Stereocenters	2 / 2
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

FC1=CN=CC(=C1)N([C@H](C(=O)NC2CC(F)(F)C2)C3=CC=CC=C3Cl)C(=O)[C@@H]4CCC(=O)N4C5=NC=CC(=C5)C#N

InChI

InChIKey=WIJZXSAJMHAVGX-DHLKQENFSA-N

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

HIDE SMILES / InChI

Description
Sources: https://www.ncbi.nlm.nih.gov/pubmed/25583779
Curator's Comment: Description was created using several sources including: https://www.ncbi.nlm.nih.gov/pubmed/25980580 | http://www.bloodjournal.org/content/124/21/3734

Ivosidenib (AG-120) is an inhibitor of isocitrate dehydrogenase 1 (IDH1) This experimental drug inhibits mutant IDH1, leading to increased differentiation and decreased proliferation in IDH1 positive tumors and thus is thought to be promising for the treatment of IDH1-mutated tumors. In vivo treatment with AG-120 of TF-1 cells, primary human AML patient samples expressing mutant IDH1 and primary human blast cells cultured ex vivo showed that AG-120 is effective at lowering 2-HG levels and restoring cellular differentiation. It showed promising results in a phase I trial in patients with relapsed or refractory acute myeloid leukemia and is being evaluated in Phase III in previously-treated subjects with nonresectable or metastatic cholangiocarcinoma with an IDH1 mutation.

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
isocitrate dehydrogenase 1 (NADP+), soluble 1 Target ID: 1.04387424E8 Gene Symbol: IDH1 Sources: http://www.bloodjournal.org/content/126/23/1306	Inhibitor 8297

Conditions

Condition	Modality	Targets	Highest Phase	Product
Relapsed or refractory acute myeloid leukemia 1 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/211192s000lbl.pdf	Primary		Approved 8429	TIBSOVO Approved Use TIBSOVO is an isocitrate dehydrogenase-1 (IDH1) inhibitor indicated for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) with a susceptible IDH1 mutation as detected by an FDA-approved test. Launch Date 2018
Cholangiocarcinoma 17 Sources: https://clinicaltrials.gov/ct2/show/NCT02989857	Primary		Phase III 656	Unknown Approved Use Unknown

C_max

Value	Dose	Co-administered	Analyte	Population
3657 ng/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/31028664	500 mg single, oral dose: 500 mg route of administration: Oral experiment type: SINGLE co-administered:		IVOSIDENIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

AUC

Value	Dose	Co-administered	Analyte	Population
112490 ng × h/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/31028664	500 mg single, oral dose: 500 mg route of administration: Oral experiment type: SINGLE co-administered:		IVOSIDENIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

T_1/2

Value	Dose	Co-administered	Analyte	Population
64.3 h EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/31028664	500 mg single, oral dose: 500 mg route of administration: Oral experiment type: SINGLE co-administered:		IVOSIDENIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

F_unbound

Value	Dose	Co-administered	Analyte	Population
6% DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/211192s001lbl.pdf			IVOSIDENIB plasma	Homo sapiens population: UNKNOWN age: UNKNOWN sex: UNKNOWN food status: UNKNOWN

Doses

Dose	Population	Adverse events
1200 mg single, oral Highest studied dose Dose: 1200 mg Route: oral Route: single Dose: 1200 mg Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/211192Orig1s000MultidisciplineR.pdf Page: 52	unhealthy, adult n = 4 Health Status: unhealthy Condition: acute myeloid leukemia Age Group: adult Sex: unknown Population Size: 4 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/211192Orig1s000MultidisciplineR.pdf Page: 52	Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/211192Orig1s000MultidisciplineR.pdf Page: 52
500 mg 1 times / day steady, oral Recommended Dose: 500 mg, 1 times / day Route: oral Route: steady Dose: 500 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/211192s000lbl.pdf Page: 6.1	unhealthy, adult n = 179 Health Status: unhealthy Condition: acute myeloid leukemia Age Group: adult Sex: unknown Population Size: 179 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/211192s000lbl.pdf Page: 6.1	Disc. AE: Guillain Barre syndrome, Rash... Other AEs: QT prolonged, Differentiation syndrome... AEs leading to discontinuation/dose reduction: Guillain Barre syndrome (1%) Rash (1%) Stomatitis (1%) Creatinine increased (1%) Other AEs: QT prolonged (7%) Differentiation syndrome (3%) Leukocytosis (3%) Dyspnea (3%) QT prolonged (1%) Diarrhea (1%) Nausea (1%) Decreased hemoglobin (1%) Transaminases increased (1%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/211192s000lbl.pdf Page: 6.1
500 mg 1 times / day steady, oral Recommended Dose: 500 mg, 1 times / day Route: oral Route: steady Dose: 500 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/211192s000lbl.pdf Page: Table 2	unhealthy, adult n = 179 Health Status: unhealthy Condition: acute myeloid leukemia Age Group: adult Sex: unknown Population Size: 179 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/211192s000lbl.pdf Page: Table 2	Other AEs: Leukocytosis, Differentiation syndrome... Other AEs: Leukocytosis (all grades, 38%) Differentiation syndrome (all grades, 19%) Diarrhea (all grades, 34%) Nausea (all grades, 31%) Mucositis (all grades, 28%) Constipation (all grades, 20%) Vomiting (all grades, 18%) Abdominal pain (all grades, 16%) Fatigue (all grades, 39%) Edema (all grades, 32%) Pyrexia (all grades, 23%) Chest pain (all grades, 16%) Electrocardiogram QT prolonged (all grades, 26%) Decreased appetite (all grades, 18%) Tumor lysis syndrome (all grades, 8%) Arthralgia (all grades, 36%) Myalgia (all grades, 18%) Headache (all grades, 16%) Neuropathy (all grades, 12%) Cough (all grades, 22%) Dyspnea (all grades, 33%) Pleural effusion (all grades, 13%) Rash (all grades, 26%) Hypotension (all grades, 12%) Leukocytosis (grade 3-4, 8%) Differentiation syndrome (grade 3-4, 13%) Diarrhea (grade 3-4, 2%) Nausea (grade 3-4, 1%) Mucositis (grade 3-4, 3%) Constipation (grade 3-4, 1%) Vomiting (grade 3-4, 1%) Abdominal pain (grade 3-4, 1%) Fatigue (grade 3-4, 3%) Edema (grade 3-4, 1%) Pyrexia (grade 3-4, 1%) Chest pain (grade 3-4, 3%) Electrocardiogram QT prolonged (grade 3-4, 10%) Decreased appetite (grade 3-4, 2%) Tumor lysis syndrome (grade 3-4, 6%) Arthralgia (grade 3-4, 4%) Myalgia (grade 3-4, 1%) Neuropathy (grade 3-4, 1%) Cough (grade 3-4, <1%) Dyspnea (grade 3-4, 9%) Pleural effusion (grade 3-4, 3%) Rash (grade 3-4, 2%) Hypotension (grade 3-4, 4%) Hemoglobin decreased (all grades, 60%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/211192s000lbl.pdf Page: Table 2
500 mg 1 times / day steady, oral Recommended Dose: 500 mg, 1 times / day Route: oral Route: steady Dose: 500 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/211192s000lbl.pdf Page: Table 3	unhealthy, adult n = 179 Health Status: unhealthy Condition: acute myeloid leukemia Age Group: adult Sex: unknown Population Size: 179 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/211192s000lbl.pdf Page: Table 3	Other AEs: Sodium decreased, Magnesium decreased... Other AEs: Sodium decreased (all grades, 39%) Magnesium decreased (all grades, 38%) Uric acid increased (all grades, 32%) Potassium decreased (all grades, 31%) Alkaline phosphatase increased (all grades, 27%) Aspartate aminotransferase increased (all grades, 27%) Phosphate decreased (all grades, 25%) Creatinine increased (all grades, 23%) Alanine aminotransferase increased (all grades, 15%) Bilirubin increased (all grades, 16%) Hemoglobin decreased (grade 3-4, 46%) Sodium decreased (grade 3-4, 4%) Uric acid increased (grade 3-4, 6%) Potassium decreased (grade 3-4, 6%) Alkaline phosphatase increased (grade 3-4, 1%) Aspartate aminotransferase increased (grade 3-4, 1%) Phosphate decreased (grade 3-4, 8%) Creatinine increased (grade 3-4, 1%) Alanine aminotransferase increased (grade 3-4, 1%) Bilirubin increased (grade 3-4, 1%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/211192s000lbl.pdf Page: Table 3
500 mg 1 times / day steady, oral Recommended Dose: 500 mg, 1 times / day Route: oral Route: steady Dose: 500 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/211192Orig1s000MultidisciplineR.pdf Page: 122	unhealthy, adult n = 179 Health Status: unhealthy Condition: acute myeloid leukemia Age Group: adult Sex: unknown Population Size: 179 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/211192Orig1s000MultidisciplineR.pdf Page: 122	Disc. AE: Sepsis, Fungal infection... AEs leading to discontinuation/dose reduction: Sepsis (grade 4, 2%) Fungal infection (2%) Pneumonia (2%) Renal insufficiency (1%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/211192Orig1s000MultidisciplineR.pdf Page: 122
500 mg 1 times / day steady, oral Recommended Dose: 500 mg, 1 times / day Route: oral Route: steady Dose: 500 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/211192Orig1s000MultidisciplineR.pdf Page: Table 3	unhealthy, adult n = 179 Health Status: unhealthy Condition: acute myeloid leukemia Age Group: adult Sex: unknown Population Size: 179 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/211192Orig1s000MultidisciplineR.pdf Page: Table 3	Other AEs: Infections and infestations, Blood and lymphatic system disorders... Other AEs: Infections and infestations (43%) Blood and lymphatic system disorders (40%) Respiratory, thoracic and mediastinal disorders (15%) Cardiac disorders (11%) Gastrointestinal disorders (11%) Metabolism and nutrition disorders (8%) Nervous system disorders (8%) Musculoskeletal and connective tissue disorders (4%) Injury, poisoning and procedural complications (4%) Renal and urinary disorders (4%) Vascular disorders (3%) Neoplasm (2%) Skin and subcutaneous tissue disorders (2%) Immune system disorders (1%) Psychiatric disorders (1%) Ear and labyrinth disorders (1%) Hepatobiliary disorders (1%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/211192Orig1s000MultidisciplineR.pdf Page: Table 3

AEs

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
	inducer 389 inhibitor 1767	inhibitor 1852	inhibitor 1612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
BCRP 699 OATP1B1 788 OATP1B3 706 OAT1 599 OCT2 647 OAT3 642 P-gp 1461 CYP2C8 911 CYP2C19 1478 CYP3A4/5 278 CYP1A2 1524 CYP2B6 810 Cav1.2 45	CYP3A 191 CYP2B6 664 CYP2C8 693	CYP2B6 547 CYP2C8 168 CYP1A2 701 CYP2C19 293

Drug as perpetrator

Target	Modality	Activity
CYP2C19 1553	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/211192Orig1s000MultidisciplineR.pdf#page=176 Page: 176.0	inconclusive
OATP1B3 715	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/211192Orig1s000MultidisciplineR.pdf#page=67 Page: 67.0	no [Ki 22.8 uM]
OATP1B1 803	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/211192Orig1s000MultidisciplineR.pdf#page=67 Page: 67.0	no [Ki 9.56 uM]
BCRP 773	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/211192Orig1s000MultidisciplineR.pdf#page=67 Page: 67.0	no
CYP1A2 1692	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/211192Orig1s000MultidisciplineR.pdf#page=176 Page: 176.0	no
CYP1A2 1692	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/211192Orig1s000MultidisciplineR.pdf#page=176 Page: 176.0	no
CYP2B6 1001	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/211192Orig1s000MultidisciplineR.pdf#page=176 Page: 176.0	no
CYP2C9 1819	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/211192Orig1s000MultidisciplineR.pdf#page=176 Page: 176.0	no
OAT1 603	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/211192Orig1s000MultidisciplineR.pdf#page=67 Page: 67.0	no
OCT2 648	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/211192Orig1s000MultidisciplineR.pdf#page=67 Page: 67.0	no
OAT3 644	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/211192Orig1s000MultidisciplineR.pdf#page=67 Page: 67.0	yes [Ki 0.322 uM]
P-gp 1650	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/211192Orig1s000MultidisciplineR.pdf#page=67 Page: 67.0	yes [Ki 19.6 uM]
CYP2B6 1001	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/211192Orig1s000MultidisciplineR.pdf#page=67 Page: 67.0	yes
CYP2C19 1553	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/211192Orig1s000MultidisciplineR.pdf#page=176 Page: 176.0	yes
CYP2C8 965	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/211192Orig1s000MultidisciplineR.pdf#page=67 Page: 67.0	yes
CYP2C8 965	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/211192Orig1s000MultidisciplineR.pdf#page=176 Page: 176.0	yes
CYP2C9 1819	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/211192Orig1s000MultidisciplineR.pdf#page=67 Page: 67.0	yes
CYP2D6 1891	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/211192Orig1s000MultidisciplineR.pdf#page=176 Page: 176.0	yes
CYP3A4/5 335	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/211192Orig1s000MultidisciplineR.pdf#page=176 Page: 176.0	yes

Drug as victim

Target	Modality	Activity
CYP2B6 664	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/211192Orig1s000MultidisciplineR.pdf#page=176 Page: 176.0	minor
CYP2C8 693	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/211192Orig1s000MultidisciplineR.pdf#page=176 Page: 176.0	minor
CYP3A 191	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/211192Orig1s000MultidisciplineR.pdf#page=65 Page: 65.0	yes

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
Cav1.2 49	inhibitor 1626 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/211192Orig1s000MultidisciplineR.pdf#page=38 Page: 38.0
hERG 1647	inhibitor 1626 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/211192Orig1s000MultidisciplineR.pdf#page=38 Page: 38.0

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:145430	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:145430
ChemicalBook	CB32738771	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB32738771
MolPort	MolPort-044-560-317	https://www.molport.com/shop/molecule-link/MolPort-044-560-317
ZINC	ZINC000205136523	http://zinc15.docking.org/substances/ZINC000205136523

PubMed

Title	Date	PubMed
Evidence for Clinical Differentiation and Differentiation Syndrome in Patients With Acute Myeloid Leukemia and IDH1 Mutations Treated With the Targeted Mutant IDH1 Inhibitor, AG-120.	2016 Aug	27245312

Patents

Sample Use Guides

In Vivo Use Guide

Patients in the study were given either 100 mg of AG-120 twice daily, or 300 mg, 500 mg, or 800 mg once daily, over continuous 28-day cycles.

Route of Administration: Oral

In Vitro Use Guide

TF-1 cells or primary human AML patient samples expressing mutant IDH1 were treated with 0.5, 1.0, and 5.0 uM of AG-120 which decreased intracellular 2-HG levels, inhibited growth factor independent proliferation and restored erythropoietin (EPO)-induced differentiation in TF-1 IDH1-R132H cells.

Name

Type

Language

IVOSIDENIB

Official Name

English

TIBSOVO

Brand Name

English

GLYCINAMIDE, 1-(4-CYANO-2-PYRIDINYL)-5-OXO-L-PROLYL-2-(2-CHLOROPHENYL)-N-(3,3-DIFLUOROCYCLOBUTYL)-N2-(5-FLUORO-3-PYRIDINYL)-, (2S)-

Systematic Name

English

IVOSIDENIB [USAN]

Common Name

English

AG-120

Code

English

ivosidenib [INN]

Common Name

English

IVOSIDENIB [MI]

Common Name

English

Ivosidenib [WHO-DD]

Common Name

English

IVOSIDENIB [ORANGE BOOK]

Common Name

English

(2S)-N-{(1S)-1-(2-Chlorophenyl)-2-[(3,3-difluorocyclobutyl)amino]-2-oxoethyl}-1-(4-cyanopyridin-2-yl)-N-(5-fluoropyridin-3-yl)-5-oxopyrrolidine-2-carboxamide

Systematic Name

English

Classification Tree Code System Code

FDA ORPHAN DRUG

562216