Futibatinib API Manufacturers

General Description:

Futibatinib, identified by CAS number 1448169-71-8, is a notable compound with significant therapeutic applications. Futibatinib is an inhibitor of Fibroblast Growth Factor receptor (FGFR), which comprises a group of receptor tyrosine kinases that play a key role in cell proliferation, differentiation, migration, and survival. FGFR was investigated in oncology as a therapeutic target, as FGFR genomic aberrations and dysregulated FGFR signalling pathways are observed in some cancers such as cholangiocarcinoma and urothelial malignancies. As a novel inhibitor of FGFR, futibatinib was first approved by the FDA in September 2022 to treat different types of intrahepatic cholangiocarcinoma.

Indications:

This drug is primarily indicated for: Futibatinib is indicated to treat adults with previously treated, unresectable, locally advanced or metastatic intrahepatic cholangiocarcinoma harboring fibroblast growth factor receptor 2 (FGFR2) gene fusions or other rearrangements. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s). Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Futibatinib undergoes metabolic processing primarily in: _In vitro_, futibatinib is primarily metabolized by CYP3A and to a lesser extent by CYP2C9 and CYP2D6. Unchanged futibatinib is the major drug-related moiety in plasma (accounting for 59% of radioactivity) in healthy subjects. This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Futibatinib are crucial for its therapeutic efficacy: T_max ranges from 1.2 to 22.8 hours, with a median value of two hours. In healthy subjects, a high-fat and high-calorie meal (900 to 1000 calories with approximately 50% of total caloric content from fat) decreased futibatinib AUC by 11% and C_max by 42%. The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Futibatinib is an important consideration for its dosing schedule: The mean (CV%) elimination half-life (t_1/2) of futibatinib is 2.9 hours (27%). This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Futibatinib exhibits a strong affinity for binding with plasma proteins: Futibatinib is 95% bound to human plasma protein at 0.2 to 5 µmol/L _in vitro_, primarily to albumin and α1-acid glycoprotein. This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Futibatinib from the body primarily occurs through: Following a single oral dose of 20 mg radiolabeled futibatinib, approximately 91% of the total recovered radioactivity was observed in feces and 9% in urine, with negligible unchanged futibatinib in urine or feces. Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Futibatinib is distributed throughout the body with a volume of distribution of: The geometric mean (CV%) apparent volume of distribution (Vc/F) is 66 L (18%). This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Futibatinib is a critical factor in determining its safe and effective dosage: The geometric mean (CV%) apparent clearance (CL/F) is 20 L/h (23%). It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Futibatinib exerts its therapeutic effects through: Futibatinib is an anticancer agent with demonstrated anti-tumour activity in mouse and rat xenograft models of human tumours with activating FGFR genetic alterations. Futibatinib is not expected to affect cell lines with no FGFR genomic aberrations. It suppresses the growth of tumours in a dose-dependent manner. The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Futibatinib functions by: Fibroblast Growth Factor receptor (FGFR) pathway play a key role in cell proliferation, differentiation, migration, and survival. Notably, FGFR genomic aberrations and aberrant FGFR signalling pathways are observed in some cancers, as constitutive FGFR signalling can support the proliferation and survival of malignant cells. Futibatinib is a selective, irreversible inhibitor of FGFR 1, 2, 3, and 4 with IC₅₀ values of less than 4 nM. It binds to the FGFR kinase domain by forming a covalent bond with cysteine in the ATP-binding pocket. Upon binding to FGFR, futibatinib blocks FGFR phosphorylation and downstream signalling pathways, such as the RAS-dependent mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3KCA)/Akt/mTOR, phospholipase Cγ (PLCγ), and JAK/STAT. Futibatinib ultimately decreases cell viability in cancer cell lines with FGFR alterations, including FGFR fusions or rearrangements, amplifications, and mutations. This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Categories:

Futibatinib is categorized under the following therapeutic classes: Antineoplastic Agents, Antineoplastic and Immunomodulating Agents, BCRP/ABCG2 Substrates, Cytochrome P-450 CYP2C9 Substrates, Cytochrome P-450 CYP2D6 Substrates, Cytochrome P-450 CYP3A Substrates, Cytochrome P-450 CYP3A4 Substrates, Cytochrome P-450 Substrates, Fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitors, P-glycoprotein inhibitors, P-glycoprotein substrates, Protein Kinase Inhibitors. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.