Over 92% of Ivosidenib is present in circulation as the parent drug. Metabolism occurs primarily through CYP3A4 with some contribution from N-dealkylation and hydrolysis.
Ivosidenib does not appear to be mutagenic or clastogenic. 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. 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, 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. 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. <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.
Elevations in serum aminotransferase levels are common during ivosidenib therapy occurring in 15% to 20% of patients, but rising above 5 times the upper limit of the normal range in only 1% to 2%. Ivosidenib has had limited clinical use but has not been linked to instances of acute liver injury with symptoms or jaundice. Because of the limited clinical experience with the use of IDH inhibitors, their potential for causing liver injury is not well defined.
In prelicensure studies, ivosidenib therapy was associated with "differentiation syndrome" in 5% of patients, which was sometimes severe and life-threatening. Differentiation syndrome is marked by rapid proliferation of myeloid cells and symptoms of respiratory distress, accompanied by hypoxia, pulmonary infiltrates and pleural effusions. Other manifestations include renal impairment, fever, lymphadenopathy, bone pain, peripheral edema and weight gain. Liver dysfunction can also occur but is generally 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 stopping ivosidenib and use of corticosteroids and hydroxyurea in more severe cases. Patients can be restarted on ivosidenib once the syndrome resolves.
Likelihood score: E* (unproven but suspected cause of clinically apparent liver injury).
来源:LiverTox
毒理性
蛋白质结合
伊沃西替尼与血浆蛋白的结合率在体外测定为92-96%。
Ivosidenib is 92-96% bound to plasma proteins as determined in vitro.
Ivosidenib has a Tmax of 3 hours following oral administration of a 2 250 mg tablets (total 500 mg). 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. 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.
Following oral administration, 77% of Ivosidenib is eliminated in the feces with 67% present as the parent drug. 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. Changes in patients with severe renal impairment or moderate too severe hepatic impairment have not been investigated.
来源:DrugBank
吸收、分配和排泄
分布容积
艾伏西尼布在稳态下的平均表观分布容积为234升。
Ivosidenib has a mean apparent Vd of 234 L at steady-state.
来源:DrugBank
吸收、分配和排泄
清除
艾伏西尼布的表观清除率为4.3升/小时。
Ivosidenib has an apparent clearance rate of 4.3 L/h
THERAPEUTICALLY ACTIVE COMPOUNDS AND THEIR METHODS OF USE
申请人：Lemieux Rene M.
公开号：US20150031627A1
公开（公告）日：2015-01-29
Provided are methods of treating a cancer characterized by the presence of a mutant allele of IDH1/2 comprising administering to a subject in need thereof a compound described here.
[EN] THERAPEUTICALLY ACTIVE COMPOUNDS AND THEIR METHODS OF USE<br/>[FR] COMPOSÉS THÉRAPEUTIQUEMENT ACTIFS ET LEURS MÉTHODES D'UTILISATION
申请人：AGIOS PHARMACEUTICALS INC
公开号：WO2015010297A1
公开（公告）日：2015-01-29
Provided are methods of treating a cancer characterized by the presence of a mutant allele of IDH1/2 comprising administering to a subject in need thereof a compound described here.
[EN] THERAPEUTICALLY ACTIVE COMPOUNDS AND THEIR METHODS OF USE<br/>[FR] COMPOSÉS THÉRAPEUTIQUEMENT ACTIFS ET LEURS PROCÉDÉS D'UTILISATION
申请人：AGIOS PHARMACEUTICALS INC
公开号：WO2013107291A1
公开（公告）日：2013-07-25
Provided are methods of treating a cancer characterized by the presence of a mutant allele of IDH1/2 comprising administering to a subject in need thereof a compound described here.
[EN] THERAPEUTICALLY ACTIVE COMPOUNDS AND USE THEREOF<br/>[FR] COMPOSÉS THÉRAPEUTIQUEMENT ACTIFS ET UTILISATION DE CEUX-CI
申请人：AGIOS PHARMACEUTICALS INC
公开号：WO2015010626A1
公开（公告）日：2015-01-29
Provided are therapeutically active compounds and the use in manufacture of medicaments for treating a cancer characterized by the presence of a mutant allele of IDH1.
提供的是治疗上有效的化合物及其在制造用于治疗具有IDH1突变等位基因的癌症的药物中的应用。
[EN] NEW ISOINDOLINE OR ISOQUINOLINE COMPOUNDS, A PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM<br/>[FR] NOUVEAUX COMPOSÉS ISOINDOLINE OU ISOQUINOLÉINE, PROCÉDÉ POUR LEUR PRÉPARATION ET COMPOSITIONS PHARMACEUTIQUES LES CONTENANT
申请人：SERVIER LAB
公开号：WO2015011164A1
公开（公告）日：2015-01-29
Compounds of formula (I): (I) wherein Het, R3, R4, R5, R7, R8, R9, T, p, p', q, and q' are as defined in the description are pro-apoptotic agents useful in the treatment of cancers and of auto-immune and immune system diseases.
