Numerous IDH1-R132 mutants (R132H, R132C, R132G, and R132L) can effectively be inhibited from producing 2-HG by olutasidenib (FT-2102), suggesting that Olutasidenib (FT-2102) is effective against the majority of tumors expressing IDH1-R132 mutants. IDH1 isoforms are the only ones that olintasidenib (FT-2102) significantly inhibits, with no discernible effect on wild-type IDH1 (> 20 µM) or IDH2 mutants (R172K and R140Q, both > 20 µM) [2].

Three oral doses of olinusidenib (FT-2102; 25 mg/kg, 50 mg/kg, and 12 hours apart) showed strong antitumor activity in xenografted female BALB/c nude mice with the HCT116-IDH1-R132H/+ mutation [2].

Animal/Disease Models: HCT116-IDH1-R132H/+ xenograft-bearing female BALB/c nude mice [2].
Doses: 12.5, 25 and 50 mg/kg.
Doses: Orally administered 3 times (12.5, 25 and 50 mg/kg) every 12 hrs (hrs (hours)).
Experimental Results: Demonstrated time- and dose-dependent inhibition of 2-HG levels in tumors. At the highest dose tested in these studies (50 mg/kg), FT-2102 treatment inhibited 2-HG levels in tumors by >90% within 24 hrs (hrs (hours)) of the last dose in HCT116-IDH1-R132H/+ Xenograft model.

Absorption, Distribution and Excretion
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 Cmax is 3573 ng/mL. The Cmax 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 tmax 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 Cmax and AUCinf, respectively.
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).
Olutasidenib has an apparent volume of distribution of 319 L.
Olutasidenib has a mean apparent oral clearance (CL/F) of 4 L/h.

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Metabolism / Metabolites
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.

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Biological Half-Life
Olutasidenib has a mean half-life of 67 hours.

Hepatotoxicity
In the published preregistration clinical trials of olutasidenib, rates of serum ALT or AST elevations were 46% and 47% which were above 5 times the upper limit of normal (ULN) in 13% and 10%, resulting in dose modification in at least 10% of patients and discontinuation ultimately in 5% of patients. One individual treated with the combination of azacytidine and olutasidenib died of hepatic failure, and another developed a clinically apparent but self-limited episode of cholestatic hepatitis. Most hepatic effects occurred early during therapy, usually during the first or second month, but isolated instances arose as late as 5 months after starting olutasidenib. Since its approval and general availability, at least one other case of acute hepatitis with jaundice has been reported from clinical trials of olutasidenib.
In prelicensure studies, olutasidenib therapy was also associated with “differentiation syndrome” in 9% to 16% of patients that was sometimes severe and occasionally fatal. Differentiation syndrome is the result of the sudden and rapid proliferation of myeloid cells results in release of inflammatory cytokines and symptoms of respiratory distress, accompanied by hypoxia, pulmonary infiltrates, and pleural effusions. Other manifestations include fever, renal impairment, lymphadenopathy, bone pain, peripheral edema, and weight gain. Liver dysfunction can also occur but is usually overshadowed by the more severe systemic manifestations. The onset of differentiation syndrome is generally within 2 to 8 weeks of starting therapy, and the course can be severe. Management includes prompt discontinuation of therapy and use of corticosteroids in more severe cases. Patients can be restarted on olutasidenib once the syndrome resolves. Olutasidenib has a black box warning of differentiation syndrome with specific recommendations for its prompt recognition and management. The label also warns about the risk of hepatotoxicity with recommendation to monitor liver tests during treatment and interrupt and reduce or discontinue if hepatotoxicity occurs.
Likelihood score: D (possible but uncommon cause of clinically apparent liver injury).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
No information is available on the use of olutasidenib during breastfeeding. Because it is 93% bound to plasma proteins, the amount in milk is likely to be low. However, The manufacturer recommends that the mother not breastfeed during treatment and for 2 weeks after the last dose.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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Protein Binding
The plasma protein binding of olutasidenib is approximately 93%.

[1]. A phase 1 dose escalation study of the IDH1m inhibitor, FT-2102, in patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS).

[2]. Structure-based design and identification of FT-2102 (olutasidenib), a potent mutant-selective IDH1 inhibitor. J Med Chem. 2020.

Olutasidenib (FT-2102) is a selective and potent isocitrate dehydrogenase-1 (IDH1) inhibitor approved by the FDA in December 2022. 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. 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. Olutasidenib inhibits the mutated IDH1 specifically, and provides a therapeutic benefit in IDH1-mutated cancers. Other IDH1 inhibitors, such as [ivosidenib], have also been approved for the treatment of relapsed or refractory AML. 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).
Olutasidenib is a small molecule inhibitor of mutated isocitrate dehydrogenase-1 (IDH1) that is used in the treatment of adults with relapsed or refractory acute myelogenous leukemia with mutated IDH1. Olutasidenib is associated with a high rate of serum aminotransferase elevations during therapy that can be severe and require early discontinuation and occasionally have led to clinically apparent acute liver injury.
Olutasidenib is an orally available inhibitor of isocitrate dehydrogenase type 1 (IDH1; IDH-1; IDH1 [NADP+] soluble) with a mutation at arginine (R) 132, IDH1(R132), with potential antineoplastic activity. Upon administration, olutasidenib specifically inhibits IDH1(R132), thereby inhibiting the formation of the oncometabolite 2-hydroxyglutarate (2HG) from alpha-ketoglutarate (a-KG). This prevents 2HG-mediated signaling and leads to both an induction of cellular differentiation and an inhibition of cellular proliferation in tumor cells expressing IDH(R132). IDH1(R132) mutations are highly expressed in certain malignancies, including gliomas; they initiate and drive cancer growth by both blocking cell differentiation and catalyzing the formation of 2HG.

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Drug 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.

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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. 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.

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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.

C18H15CLN4O2

354.79030251503

354.09

C, 60.94; H, 4.26; Cl, 9.99; N, 15.79; O, 9.02

1887014-12-1

118955396

Light yellow to yellow solid powder

2.5

2

4

3

25

745

1

C[C@@H](C1=CC2=C(C=CC(=C2)Cl)NC1=O)NC3=CC=C(N(C3=O)C)C#N

NEQYWYXGTJDAKR-JTQLQIEISA-N

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

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

FT-2102; FT 2102; FT2102

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~125 mg/mL (~352.32 mM)

Solubility in Formulation 1: ≥ 2.08 mg/mL (5.86 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.08 mg/mL (5.86 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)