Olutasidenib (FT2102)   中文名称: 奥鲁他赛尼

奥他西地尼 (FT-2102) 可有效抑制许多 IDH1-R132 突变体（R132H、R132C、R132G 和 R132L）产生 2-HG，这表明奥他西地尼 (FT-2102) 对大多数表达 IDH1-的肿瘤有效。 R132突变体。 IDH1 亚型是 olintasidenib (FT-2102) 显着抑制的唯一亚型，对野生型 IDH1 (> 20 µM) 或 IDH2 突变体（R172K 和 R140Q，均 > 20 µM）没有明显影响 [2]。

三种口服剂量的 olinusidenib（FT-2102；25 mg/kg、50 mg/kg，间隔 12 小时）在具有 HCT116-IDH1-R132H/+ 突变的异种移植雌性 BALB/c 裸鼠中显示出强大的抗肿瘤活性 [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.

---

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.

---

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).

---

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.

---

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.

---

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.

---

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.

---

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

85.2

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)

配方 1 中的溶解度: ≥ 2.08 mg/mL (5.86 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 20.8 mg/mL澄清DMSO储备液加入400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

---

配方 2 中的溶解度: ≥ 2.08 mg/mL (5.86 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 20.8 mg/mL 澄清 DMSO 储备液加入到 900 μL 玉米油中并混合均匀。

---

请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。