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Ivosidenib | CAS No: 1448347-49-6 | GMP-certified suppliers
A medication that treats IDH1-mutated acute myeloid leukemia, myelodysplastic syndromes, and advanced cholangiocarcinoma, offering targeted therapy for patients with limited treatment options.
Therapeutic categories
Amino AcidsAmino Acids, Peptides, and ProteinsAntineoplastic AgentsAntineoplastic and Immunomodulating AgentsCytochrome P-450 CYP2B6 InducersCytochrome P-450 CYP2B6 Inducers (strength unknown)
Generic name
Ivosidenib
Molecule type
small molecule
CAS number
1448347-49-6
DrugBank ID
DB14568
Approval status
Approved drug, Investigational drug
ATC code
L01XX62
Primary indications
- Ivosidenib is an isocitrate dehydrogenase-1 (IDH1) inhibitor approved for use in the US and Europe
- It is indicated for the treatment of patients with a susceptible IDH1 mutation with:
- Newly Diagnosed Acute Myeloid Leukemia (AML)** in combination [azacitidine] or as monotherapy for the treatment of newly diagnosed AML in adults who have comorbidities that preclude the use of intensive induction chemotherapy
- [L41870, L46591] this indication is reserved for adults 75 years or older in the US
Product Snapshot
- Ivosidenib is an oral small molecule formulation delivered as film-coated tablets
- It is primarily indicated for the treatment of patients with IDH1-mutated acute myeloid leukemia (AML), relapsed or refractory myelodysplastic syndromes, and previously treated locally advanced or metastatic cholangiocarcinoma
- Ivosidenib is approved for use in key regulatory markets including the US and Europe (FDA and EMA approved)
Clinical Overview
Ivosidenib (CAS number 1448347-49-6) is a targeted antineoplastic agent classified as an isocitrate dehydrogenase-1 (IDH1) inhibitor. It selectively inhibits mutant forms of IDH1, an enzyme involved in cellular metabolism that, when mutated, contributes to oncogenesis through the production of the oncometabolite D-2-hydroxyglutarate (D-2HG). Elevated D-2HG levels inhibit α-ketoglutarate-dependent dioxygenases, resulting in epigenetic dysregulation via histone and DNA hypermethylation and a subsequent block in cellular differentiation. By inhibiting mutant IDH1, ivosidenib reduces D-2HG accumulation, promoting myeloid cell differentiation and disrupting malignant cell proliferation.
Ivosidenib is approved in the United States and European Union for the treatment of adult patients harboring susceptible IDH1 mutations in several clinical settings. These include newly diagnosed acute myeloid leukemia (AML) in adults unfit for intensive chemotherapy, either as monotherapy or in combination with azacitidine, relapsed or refractory AML, relapsed or refractory myelodysplastic syndromes, and locally advanced or metastatic cholangiocarcinoma previously treated with systemic therapy. Regulatory approval in Europe was granted by the EMA in 2023 following a positive CHMP opinion earlier that year.
Pharmacodynamically, ivosidenib exhibits dose-dependent inhibition of mutant IDH1 enzyme activity without significant inhibition of IDH2. It targets common mutations at residue R132, including R132H and R132C variants. Preclinical models demonstrate effective reduction of D-2HG levels and induction of differentiation in IDH1-mutated cancer cells.
Pharmacokinetic and ADME parameters include metabolic interactions whereby ivosidenib induces and is a substrate of cytochrome P450 enzymes, notably CYP3A4, with implications for drug-drug interactions. It also interacts with P-glycoprotein and organic anion transporters. The compound carries a moderate risk for QTc prolongation and exhibits a narrow therapeutic index requiring careful monitoring during clinical use.
Safety considerations include risks related to differentiation syndrome, hepatotoxicity, and QT interval prolongation. These adverse effects necessitate vigilant cardiac and hepatic monitoring during treatment.
From a sourcing perspective, API procurement should prioritize suppliers with demonstrated compliance to cGMP standards due to the compound’s narrow therapeutic index and complex mechanism. Comprehensive quality control testing for identity, purity, enantiomeric excess, and residual solvents is essential to ensure consistent clinical efficacy and safety. Given ivosidenib’s role in targeted oncology therapy, traceability and documentation supporting batch integrity are critical in maintaining regulatory compliance globally.
Ivosidenib is approved in the United States and European Union for the treatment of adult patients harboring susceptible IDH1 mutations in several clinical settings. These include newly diagnosed acute myeloid leukemia (AML) in adults unfit for intensive chemotherapy, either as monotherapy or in combination with azacitidine, relapsed or refractory AML, relapsed or refractory myelodysplastic syndromes, and locally advanced or metastatic cholangiocarcinoma previously treated with systemic therapy. Regulatory approval in Europe was granted by the EMA in 2023 following a positive CHMP opinion earlier that year.
Pharmacodynamically, ivosidenib exhibits dose-dependent inhibition of mutant IDH1 enzyme activity without significant inhibition of IDH2. It targets common mutations at residue R132, including R132H and R132C variants. Preclinical models demonstrate effective reduction of D-2HG levels and induction of differentiation in IDH1-mutated cancer cells.
Pharmacokinetic and ADME parameters include metabolic interactions whereby ivosidenib induces and is a substrate of cytochrome P450 enzymes, notably CYP3A4, with implications for drug-drug interactions. It also interacts with P-glycoprotein and organic anion transporters. The compound carries a moderate risk for QTc prolongation and exhibits a narrow therapeutic index requiring careful monitoring during clinical use.
Safety considerations include risks related to differentiation syndrome, hepatotoxicity, and QT interval prolongation. These adverse effects necessitate vigilant cardiac and hepatic monitoring during treatment.
From a sourcing perspective, API procurement should prioritize suppliers with demonstrated compliance to cGMP standards due to the compound’s narrow therapeutic index and complex mechanism. Comprehensive quality control testing for identity, purity, enantiomeric excess, and residual solvents is essential to ensure consistent clinical efficacy and safety. Given ivosidenib’s role in targeted oncology therapy, traceability and documentation supporting batch integrity are critical in maintaining regulatory compliance globally.
Identification & chemistry
| Generic name | Ivosidenib |
|---|---|
| Molecule type | Small molecule |
| CAS | 1448347-49-6 |
| UNII | Q2PCN8MAM6 |
| DrugBank ID | DB14568 |
Pharmacology
| Summary | Ivosidenib selectively inhibits mutant isocitrate dehydrogenase 1 (IDH1), particularly variants with R132 mutations, reducing the production of the oncometabolite D-2-hydroxyglutarate (D-2HG). By lowering D-2HG levels, it modulates epigenetic regulation through restoration of α-KG-dependent dioxygenase activity, promoting cell differentiation and counteracting oncogenic processes. Its pharmacodynamic effect involves targeting mutant IDH1-driven metabolic and epigenetic dysregulation implicated in various malignancies. |
|---|---|
| Mechanism of action | Isocitrate dehydrogenase 1 (IDH1) is a metabolic enzyme in the cytoplasm and peroxisomes that plays a role in many cellular processes, including mitochondrial oxidative phosphorylation, glutamine metabolism, lipogenesis, glucose sensing, and regulation of cellular redox status. IDH1 converts isocitrate to α-ketoglutarate (α-KG), a normal metabolite in the carboxylic acid cycle. Multiple cancers are associated with missense mutations in IDH1, leading to the substitution of the amino acid arginine 132 in the enzyme active site, acquired gain-of-function activity, and increased enzyme activity. IDH1 mutation results in the accumulation of D-2-hydroxyglutarate (D-2HG), an oncometabolite that is structurally similar to α-KG. D-2HG inhibits α-KG-dependent dioxygenases, including histone and DNA demethylases, which play a role in histone and DNA demethylation along with other cellular processes. Inhibition of these enzymes leads to histone and DNA hypermethylation and a block in cell differentiation, including hematopoietic differentiation. With histone hypermethylation, methylation-sensitive insulators cannot regulate the activation of oncogenes. Excess D-2HG ultimately interferes with cellular metabolism and alters epigenetic regulation towards oncogenesis. Ivosidenib inhibits the mutant IDH1 at much lower concentrations than the wild-type enzyme. It targets gene mutations at position R132, with R132H and R132C being the most common mutations. In mouse xenograft models of IDH1-mutated AML, ivosidenib caused a decrease in D-2HG levels in a dose-dependent manner and induced myeloid differentiation _in vitro_ and _in vivo_. Ivosidenib works to inhibit histone demethylases and restore normal methylation conditions to promote cell differentiation and oncogene regulation. |
| Pharmacodynamics | Ivosidenib is an antineoplastic agent that is effective in cancers with a susceptible IDH1 mutation, which indicates increased levels of oncometabolite D-2-hydroxyglutarate (D-2HG) in cancer cells. Ivosidenib decreases D-2HG levels in a dose-dependent manner by inhibiting the IDH1 enzyme. Ivosidenib inhibits both the mutant and wild-type IDH1 but does not inhibit IDH2. |
Targets
| Target | Organism | Actions |
|---|---|---|
| Isocitrate dehydrogenase [NADP] cytoplasmic | Humans | inhibitor |
ADME / PK
| Absorption | Following oral administration, ivosidenib is rapidly absorbed. The C<sub>max</sub> following a single oral dose is 4503 ng/mL in patients with relapsed or refractory AML, 4820 ng/mL in patients with newly diagnosed AML who were also treated with azacitidine, and 4060 ng/mL in patients with cholangiocarcinoma. The steady-state was reached within 14 days. The steady-state C<sub>max</sub> is 6551 ng/mL in patients with relapsed or refractory AML, 6145 ng/mL in patients with newly diagnosed AML who were also treated with azacitidine, and 4799 ng/mL in patients with cholangiocarcinoma. The T<sub>max</sub> ranges from two to three hours. A high-fat meal increases ivosidenib exposure. |
|---|---|
| Half-life | The terminal half-life at steady state is 58 hours in patients with relapsed or refractory AML, 98 hours in patients with newly diagnosed AML who were also treated with azacitidine, and 129 hours in patients with cholangiocarcinoma. |
| Protein binding | _In vitro_, ivosidenib is 92-96% bound to plasma proteins. |
| Metabolism | Ivosidenib is predominantly metabolized by CYP3A4 via oxidation. The exact chemical structures of the metabolites formed from CYP3A4-mediated oxidation have not been fully characterized. Ivosidenib can also undergo N-dealkylation and hydrolysis as minor metabolic pathways. |
| Route of elimination | Following oral administration of ivosidenib, about 77% of the dose was eliminated in feces, where 67% was in the form of unchanged parent drug. About 17% of the dose was excreted in urine, where 10% was in the form of unchanged ivosidenib. |
| Volume of distribution | The apparent volume of distribution at steady state is 403 L in patients with relapsed or refractory AML, 504 L in patients with newly diagnosed AML who were also treated with azacitidine, and 706 L in patients with cholangiocarcinoma. |
| Clearance | The apparent clearance at steady state is 5.6 L/h in patients with relapsed or refractory AML, 4.6 L/h in patients with newly diagnosed AML who were also treated with azacitidine, and 6.1 L/h in patients with cholangiocarcinoma. |
Formulation & handling
- Ivosidenib is a small molecule oral drug formulated as film-coated tablets, not suitable for injectable use.
- The compound exhibits low water solubility and moderate lipophilicity (LogP 3.01), requiring consideration for dissolution and absorption in formulation design.
- Avoid co-administration with high-fat meals, grapefruit, or St. John's Wort due to significant CYP3A-mediated drug interaction potential affecting bioavailability.
Regulatory status
| Lifecycle | The API is currently under patent protection in the United States until 2030-2035, indicating limited generic competition in the US market, while in the EU, absence of listed patents suggests a more mature market with potential for generic availability. |
|---|
| Markets | US, EU |
|---|
Supply Chain
| Supply chain summary | Ivosidenib is an active pharmaceutical ingredient with branded products available in both the US and EU markets. The originator company holds multiple patents in the United States with expiration dates ranging from 2030 to 2035, indicating that patent protection is currently in place. This suggests that generic competition is not yet established but may become relevant closer to these patent expiry dates. |
|---|
Safety
| Toxicity | There is limited information regarding the LD<sub>50</sub> or overdose of ivosidenib. Ivosidenib is associated with a risk of differentiation syndrome, Guillain-Barre syndrome, and embryo-fetal toxicity. |
|---|
High Level Warnings:
- Limited data on LD50 and overdose potential
- Handle with appropriate precautions to minimize exposure
- Associated with risks including differentiation syndrome and Guillain-Barre syndrome
Ivosidenib is a type of Enzyme Replacements/modifiers
Enzyme replacements/modifiers are a crucial category of pharmaceutical active pharmaceutical ingredients (APIs) utilized in the treatment of various enzyme-related disorders. Enzymes play a vital role in the normal functioning of the body by catalyzing specific biochemical reactions. However, in certain medical conditions, the body may lack or produce dysfunctional enzymes, leading to serious health complications.
Enzyme replacement therapy (ERT) involves administering exogenous enzymes to compensate for the enzyme deficiency in patients. These enzymes are typically derived from natural sources or produced using recombinant DNA technology. By introducing these enzymes into the body, they can effectively substitute the missing or defective enzymes, thereby restoring normal metabolic processes.
On the other hand, enzyme modifiers are API substances that regulate the activity of specific enzymes within the body. These modifiers can either enhance or inhibit the enzyme's function, depending on the therapeutic objective. By modulating enzyme activity, these APIs can restore the balance of enzymatic reactions, leading to improved physiological outcomes.
Enzyme replacements/modifiers have shown remarkable success in treating various genetic disorders, such as Gaucher disease, Fabry disease, and lysosomal storage disorders. Additionally, they have demonstrated potential in managing enzyme deficiencies associated with rare diseases and certain types of cancer.
The development and production of enzyme replacements/modifiers involve rigorous research, formulation optimization, and adherence to stringent quality control measures. Pharmaceutical companies invest substantial resources in developing these APIs to ensure their safety, efficacy, and compliance with regulatory standards.
Overall, enzyme replacements/modifiers represent a vital therapeutic category in modern medicine, offering hope and improved quality of life for patients with enzyme-related disorders.
