Olutasidenib

Identification

Summary

Olutasidenib is an isocitrate dehydrogenase-1 (IDH1) inhibitor indicated for the treatment of patients with relapsed or refractory acute myeloid leukemia with a susceptible IDH1 mutation as detected by an FDA-approved test.

Brand Names

Rezlidhia

Generic Name

Olutasidenib

DrugBank Accession Number

DB16267

Background

Olutasidenib (FT-2102) is a selective and potent isocitrate dehydrogenase-1 (IDH1) inhibitor approved by the FDA in December 2022.^5,6 It is indicated for the treatment of relapsed or refractory acute myeloid leukemia (AML) in patients with a susceptible IDH1 mutation as determined by an FDA-approved test.⁵ IDH1 mutations are common in different types of cancer, such as gliomas, AML, intrahepatic cholangiocarcinoma, chondrosarcoma, and myelodysplastic syndromes (MDS), and they lead to an increase in 2-hydroxyglutarate (2-HG), a metabolite that participates in tumerogenesis.^1,2 Olutasidenib inhibits the mutated IDH1 specifically, and provides a therapeutic benefit in IDH1-mutated cancers.^1,5

Other IDH1 inhibitors, such as ivosidenib, have also been approved for the treatment of relapsed or refractory AML.^3,4 Olutasidenib is orally bioavailable and capable of penetrating the blood-brain barrier, and is also being evaluated for the treatment of myelodysplastic syndrome (MDS), as well as solid tumors and gliomas (NCT03684811).⁴

Type

Small Molecule

Groups

Approved, Investigational

Structure

3D

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MOLSDF3D-SDFPDBSMILESInChI

Similar Structures

Structure for Olutasidenib (DB16267)

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Weight

Average: 354.79
Monoisotopic: 354.0883534

Chemical Formula

C₁₈H₁₅ClN₄O₂

Synonyms

• (s)-5-((1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl)amino)-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile
• 2-pyridinecarbonitrile, 5-(((1s)-1-(6-chloro-1,2-dihydro-2-oxo-3-quinolinyl)ethyl)amino)-1,6-dihydro-1-methyl-6-oxo-
• 5-(((1s)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl)amino)-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile
• Olutasidenib

External IDs

• FT-2102
• FT2102

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Pharmacology

Indication

Olutasidenib is indicated for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) with a susceptible isocitrate dehydrogenase-1 (IDH1) mutation as detected by an FDA-approved test.⁵

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Associated Conditions

Indication Type	Indication	Combined Product Details	Approval Level	Age Group	Patient Characteristics	Dose Form
Treatment of	Refractory acute myeloid leukemia (aml)		••••••••••••	•••••	•••• ••••••••	•••••••
Treatment of	Relapsed acute myelogenous leukemia (aml)		••••••••••••	•••••	•••• ••••••••	•••••••

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Contraindications & Blackbox Warnings

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Pharmacodynamics

In patients with acute myeloid leukemia (AML) and IDH1 mutations, olutasidenib led to a 59.1% reduction in 2-hydroxyglutarate (2-HG) levels by pre-dose Cycle 2. The reduction in 2-HG levels was maintained throughout the treatment period. A correlation between increased olutasidenib exposure and an increased probability of differentiation syndrome and grade 3 hepatotoxicity was also detected in AML patients treated with olutasidenib. The use of olutasidenib leads to a concentration-dependent increase in QTc interval; however, the impact of this increase could not be defined since higher exposures of olutasidenib were not evaluated.⁵

Mechanism of action

Olutasidenib is an isocitrate dehydrogenase-1 (IDH1) inhibitor used to treat patients with acute myeloid leukemia (AML) and IDH1 genetic mutations associated with cancer development. IDH1 catalyzes the oxidative decarboxylation of isocitrate to form α-ketoglutarate (α-KG). However, mutations in IDH1 occur in the active catalytic sites of the arginine residues and promote the conversion of α-KG to 2-hydroxyglutarate (2-HG), an oncometabolite that leads to the formation of tumors. This causes an increase in 2-HG levels, inhibiting α-KG-dependent mechanisms, such as epigenetic regulation, collagen synthesis and cell signaling. IDH1 mutations have been detected in different types of cancers, including AML, and some of the most common IDH1 mutations in patients with AML are R132H and R132C substitutions.^1,5

Olutasidenib acts as a selective IDH1 inhibitor with affinity only towards the mutated enzyme. In vitro studies have shown that olutasidenib inhibits mutated IDH1 R132H, R132L, R132S, R132G, and R132C proteins, but not wild-type IDH1 or mutated IDH2 proteins. Through the inhibition of mutant IDH1, olutasidenib reduces 2-HG levels, which promotes the restoration of normal cellular differentiation and provides a therapeutic benefit in IDH1-mutated cancers.^1,5

Target	Actions	Organism
AIsocitrate dehydrogenase [NADP] cytoplasmic	inhibitor	Humans

Absorption

In patients with acute myeloid leukemia (AML) given the recommended dosage, the steady-state daily area under the plasma drug concentration over time curve (AUC0-12-h, ss) of olutasidenib is 43050 ng⋅h/mL, and its steady-state C_max is 3573 ng/mL. The C_max and AUC of olutasidenib increase in a less-than proportionally manner between 100 mg and 300 mg (0.33 to 1 time the recommended total daily dose); however, no changes in the recommended dosage are required. In patients given a single oral dose of 150 mg, the median t_max of olutasidenib is approximately 4 hours. In healthy subjects, the administration of a single dose (150 mg) of olutasidenib with a high-fat meal (800-1,000 calories, 50% of total caloric content of the meal from fat) leads to a 191% and 83% increase of the C_max and AUC_inf, respectively.⁵

Volume of distribution

Olutasidenib has an apparent volume of distribution of 319 L.⁵

Protein binding

The plasma protein binding of olutasidenib is approximately 93%.⁵

Metabolism

Olutasidenib is metabolized through N-dealkylation, demethylation, oxidative deamination followed by oxidation, and mono-oxidation with subsequent glucuronidation. Approximately 90% of the olutasidenib dose is metabolized by CYP3A4, while CYP2C8, CYP2C9, CYP1A2, and CYP2C19 play a minor role.⁵

Route of elimination

In healthy subjects given a single dose (150 mg) of radiolabeled olutasidenib orally, approximately 17% of olutasidenib was recovered in urine (1% unchanged), while 75% was recovered in feces (35% unchanged).⁵

Half-life

Olutasidenib has a mean half-life of 67 hours.⁵

Clearance

Olutasidenib has a mean apparent oral clearance (CL/F) of 4 L/h.⁵

Adverse Effects

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Toxicity

Toxicity information regarding olutasidenib is not readily available. Patients experiencing an overdose are at an increased risk of severe adverse effects such as differentiation syndrome and hepatotoxicity.⁵ Symptomatic and supportive measures are recommended. In vivo studies evaluating the carcinogenicity of olutasidenib have not been performed. Olutasidenib was not genotoxic in the in vitro bacterial reverse mutation and human lymphocyte micronucleus assays, nor in the in vivo rat bone marrow micronucleus assay. The effect of olutasidenib on fertility has not been evaluated. In vitro and in vivo studies showed that olutasidenib was phototoxic. Pigmented rats given olutasidenib orally for 3 consecutive days and exposed to UV light 2 hours after the last dose developed skin erythema that persisted for 72 hours.⁵

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 Olutasidenib can be increased when it is combined with Abametapir.
Abemaciclib	The metabolism of Abemaciclib can be increased when combined with Olutasidenib.
Acalabrutinib	The metabolism of Acalabrutinib can be increased when combined with Olutasidenib.
Acenocoumarol	The metabolism of Acenocoumarol can be increased when combined with Olutasidenib.
Albendazole	The metabolism of Albendazole can be increased when combined with Olutasidenib.

Food Interactions

• Take on an empty stomach. The administration of olutasidenib with a high-fat meal increases drug exposure. Take on an empty stomach at least 1 hour before or 2 hours after a meal.

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International/Other Brands

Rezlidhia (Forma Therapeutics)

Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End	Region	Image
Rezlidhia	Capsule	150 mg/1	Oral	Rigel Pharmaceuticals, Inc.	2022-12-01	Not applicable

Categories

Drug Categories

• Antineoplastic Agents
• BCRP/ABCG2 Inhibitors
• Cytochrome P-450 CYP1A2 Inducers
• Cytochrome P-450 CYP1A2 Inducers (strength unknown)
• Cytochrome P-450 CYP1A2 Substrates
• Cytochrome P-450 CYP2B6 Inducers
• Cytochrome P-450 CYP2B6 Inducers (strength unknown)
• Cytochrome P-450 CYP2C19 Substrates
• Cytochrome P-450 CYP2C8 Inducers
• Cytochrome P-450 CYP2C8 Inducers (strength unknown)
• Cytochrome P-450 CYP2C8 Substrates
• Cytochrome P-450 CYP2C9 Inducers
• Cytochrome P-450 CYP2C9 Inducers (strength unknown)
• Cytochrome P-450 CYP2C9 Substrates
• 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 Enzyme Inducers
• Cytochrome P-450 Substrates
• Enzyme Inhibitors
• Heterocyclic Compounds, Fused-Ring
• Isocitrate dehydrogenase-1 (IDH1) inhibitors
• Isocitrate Dehydrogenase-1 Inhibitors
• MATE 1 Inhibitors
• MATE 2 Inhibitors
• MATE inhibitors
• OAT3/SLC22A8 Inhibitors
• OATP1B1/SLCO1B1 Inhibitors
• OATP1B3 inhibitors
• OCT2 Inhibitors
• P-glycoprotein inhibitors
• Potential QTc-Prolonging Agents
• QTc Prolonging Agents

Classification

Not classified

Affected organisms

• Humans and other mammals

Chemical Identifiers

UNII

0T4IMT8S5Z

CAS number

1887014-12-1

InChI Key

NEQYWYXGTJDAKR-JTQLQIEISA-N

InChI

InChI=1S/C18H15ClN4O2/c1-10(21-16-6-4-13(9-20)23(2)18(16)25)14-8-11-7-12(19)3-5-15(11)22-17(14)24/h3-8,10,21H,1-2H3,(H,22,24)/t10-/m0/s1

IUPAC Name

5-{[(1S)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile

SMILES

C[C@H](NC1=CC=C(C#N)N(C)C1=O)C1=CC2=C(NC1=O)C=CC(Cl)=C2

References

Synthesis Reference

Caravella JA, et al. Structure-Based Design and Identification of FT-2102 (Olutasidenib), a Potent Mutant-Selective IDH1 Inhibitor. J Med Chem. 2020 Feb 27;63(4):1612-1623. doi: 10.1021/acs.jmedchem.9b01423. Epub 2020 Feb 12.

General References

1. Caravella JA, Lin J, Diebold RB, Campbell AM, Ericsson A, Gustafson G, Wang Z, Castro J, Clarke A, Gotur D, Josephine HR, Katz M, Kershaw M, Yao L, Toms AV, Barr KJ, Dinsmore CJ, Walker D, Ashwell S, Lu W: Structure-Based Design and Identification of FT-2102 (Olutasidenib), a Potent Mutant-Selective IDH1 Inhibitor. J Med Chem. 2020 Feb 27;63(4):1612-1623. doi: 10.1021/acs.jmedchem.9b01423. Epub 2020 Feb 12. [Article]
2. de la Fuente MI, Colman H, Rosenthal M, Van Tine BA, Levacic D, Walbert T, Gan HK, Vieito M, Milhem MM, Lipford K, Forsyth S, Guichard SM, Mikhailov Y, Sedkov A, Brevard J, Kelly PF, Mohamed H, Monga V: Olutasidenib (FT-2102) in patients with relapsed or refractory IDH1-mutant glioma: a multicenter, open-label, phase 1b/2 trial Neuro-oncology. [Article]
3. Liu X, Gong Y: Isocitrate dehydrogenase inhibitors in acute myeloid leukemia. Biomark Res. 2019 Oct 22;7:22. doi: 10.1186/s40364-019-0173-z. eCollection 2019. [Article]
4. de Nigris F, Ruosi C, Napoli C: Clinical efficiency of epigenetic drugs therapy in bone malignancies. Bone. 2021 Feb;143:115605. doi: 10.1016/j.bone.2020.115605. Epub 2020 Aug 20. [Article]
5. FDA Approved Drug Products: REZLIDHIA (olutasidenib) capsules for oral use [Link]
6. US Food & Drug Administration: FDA approves olutasidenib for relapsed or refractory acute myeloid leukemia with a susceptible IDH1 mutation [Link]

External Links

ChemSpider

72380144

BindingDB

50506474

RxNav

2623641

ChEMBL

CHEMBL4297610

PDBe Ligand

PWV

Wikipedia

Olutasidenib

PDB Entries

6u4j

Clinical Trials

Clinical Trials

Phase	Status	Purpose	Conditions	Count
2	Not Yet Recruiting	Treatment	Astrocytoma / Astrocytoma, Grade III / Astrocytoma, Grade IV / Diffuse Intrinsic Pontine Gliomas (DIPG) / Diffuse Midline Glioma, H3 K27M-Mutant / High Grade Glioma (HGG) / IDH1 Mutation / IDH1 R132 / IDH1 R132C / IDH1 R132G / IDH1 R132H / IDH1 R132L / Metastatic Brain Tumors / Oligodendroglioma / Spinal Tumors / Thalamus Tumor / WHO Grade III Gliomas / WHO Grade IV Gliomas	1
1, 2	Completed	Treatment	Acute Myeloid Leukemia / Myelodysplastic Syndrome	1
1, 2	Completed	Treatment	Cohort 1a and 1b: Glioma (Advanced Gliomas and Glioblastoma Multiforme) / Cohort 2a and 2b: Hepatobiliary Tumors (Hepatocellular Carcinoma, Bile Duct Carcinoma, Intrahepatic Cholangiocarcinoma, Other Hepatobiliary Carcinomas) / Cohort 3a and 3b: Chondrosarcoma / Cohort 4a and 4b: Intrahepatic Cholangiocarcinoma / Cohort 5a: Other Non-Central Nervous System Solid Tumors With IDH1 Mutations	1
1, 2	Withdrawn	Treatment	Acute Myeloid Leukemia / Myelodysplastic Syndrome / Recurrent Acute Myeloid Leukemia / Recurrent Myelodysplastic Syndrome / Refractory Acute Myeloid Leukemia (AML) / Refractory Myelodysplastic Syndromes	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Capsule	Oral	150 mg/1

Prices

Not Available

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)	Region
US11497743	No	2019-05-16	2039-05-16
US11376246	No	2019-05-16	2039-05-16
US11013734	No	2021-05-25	2039-05-16
US11013733	No	2021-05-25	2039-05-16
US9834539	No	2017-12-05	2035-09-18
US10532047	No	2020-01-14	2039-05-16
US11498913	No	2015-09-18	2035-09-18
US10414752	No	2019-09-17	2035-09-18
US10550098	No	2020-02-04	2035-09-18
US10959994	No	2021-03-30	2039-05-16
US11738018	No	2019-07-17	2039-07-17
US11723905	No	2019-11-12	2039-11-12

Properties

State

Solid

Experimental Properties

Property	Value	Source
water solubility	Insoluble	Label

Predicted Properties

Property	Value	Source
Water Solubility	0.0572 mg/mL	ALOGPS
logP	2.76	ALOGPS
logP	1.89	Chemaxon
logS	-3.8	ALOGPS
pKa (Strongest Acidic)	13.49	Chemaxon
pKa (Strongest Basic)	1.26	Chemaxon
Physiological Charge	0	Chemaxon
Hydrogen Acceptor Count	4	Chemaxon
Hydrogen Donor Count	2	Chemaxon
Polar Surface Area	85.23 Å2	Chemaxon
Rotatable Bond Count	3	Chemaxon
Refractivity	100 m3·mol-1	Chemaxon
Polarizability	35.12 Å3	Chemaxon
Number of Rings	3	Chemaxon
Bioavailability	1	Chemaxon
Rule of Five	Yes	Chemaxon
Ghose Filter	Yes	Chemaxon
Veber's Rule	No	Chemaxon
MDDR-like Rule	No	Chemaxon

Predicted ADMET Features

Not Available

Spectra

Mass Spec (NIST)

Not Available

Spectra

Spectrum	Spectrum Type	Splash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)	Predicted LC-MS/MS	splash10-0a4i-0089000000-16b83250a7bbecafd282
Predicted MS/MS Spectrum - 10V, Negative (Annotated)	Predicted LC-MS/MS	splash10-0udj-1619000000-c2f8aef4e6fa91b5799e
Predicted MS/MS Spectrum - 20V, Positive (Annotated)	Predicted LC-MS/MS	splash10-0a4i-0049000000-ebe7bc44573cdd272e7f
Predicted MS/MS Spectrum - 20V, Negative (Annotated)	Predicted LC-MS/MS	splash10-0f8a-5129000000-e996e813d3d824bb35dd
Predicted MS/MS Spectrum - 40V, Positive (Annotated)	Predicted LC-MS/MS	splash10-0uk9-0962000000-c624d41de7f4c9799c7c
Predicted MS/MS Spectrum - 40V, Negative (Annotated)	Predicted LC-MS/MS	splash10-001i-9330000000-0a3d19576ffd37f69f28
Predicted 1H NMR Spectrum	1D NMR	Not Applicable
Predicted 13C NMR Spectrum	1D NMR	Not Applicable

Chromatographic Properties

Collision Cross Sections (CCS)

Not Available

Targets

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Details1. Isocitrate dehydrogenase [NADP] cytoplasmic

Kind

Protein

Organism

Humans

Pharmacological action

Yes

Actions

Inhibitor

Curator comments

Olutasidenib has an affinity for mutant IDH1, but not wild-type IDH1.

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

1. Caravella JA, Lin J, Diebold RB, Campbell AM, Ericsson A, Gustafson G, Wang Z, Castro J, Clarke A, Gotur D, Josephine HR, Katz M, Kershaw M, Yao L, Toms AV, Barr KJ, Dinsmore CJ, Walker D, Ashwell S, Lu W: Structure-Based Design and Identification of FT-2102 (Olutasidenib), a Potent Mutant-Selective IDH1 Inhibitor. J Med Chem. 2020 Feb 27;63(4):1612-1623. doi: 10.1021/acs.jmedchem.9b01423. Epub 2020 Feb 12. [Article]
2. de la Fuente MI, Colman H, Rosenthal M, Van Tine BA, Levacic D, Walbert T, Gan HK, Vieito M, Milhem MM, Lipford K, Forsyth S, Guichard SM, Mikhailov Y, Sedkov A, Brevard J, Kelly PF, Mohamed H, Monga V: Olutasidenib (FT-2102) in patients with relapsed or refractory IDH1-mutant glioma: a multicenter, open-label, phase 1b/2 trial Neuro-oncology. [Article]
3. FDA Approved Drug Products: REZLIDHIA (olutasidenib) capsules for oral use [Link]

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Drug created at December 15, 2020 18:17 / Updated at February 15, 2023 07:39