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General Description:

Infigratinib, identified by CAS number 872511-34-7, is a notable compound with significant therapeutic applications. Infigratinib is a pan-fibroblast growth factor receptor (FGFR) kinase inhibitor. By inhibiting the FGFR pathway, which is often aberrated in cancers such as cholangiocarcinoma, infigratinib suppresses tumour growth. Cholangiocarcinoma is the most common primary malignancy affecting the biliary tract and the second most common primary hepatic malignancy. Infitratinib is a pan-FGFR inhibitor, as it is an ATP-competitive inhibitor of all four FGFR receptor subtypes. On May 28, 2021, the FDA granted accelerated approval to infigratinib - under the market name Truseltiq - for the treatment of previously treated, unresectable locally advanced or metastatic cholangiocarcinoma in adults with a fibroblast growth factor receptor 2 (FGFR2) fusion or another rearrangement as detected by an FDA-approved test. This approval follows , another FGFR inhibitor approved by the FDA for the same therapeutic indication.

Indications:

This drug is primarily indicated for: Infigratinib is indicated for the treatment of previously treated, unresectable locally advanced or metastatic cholangiocarcinoma in adults with a fibroblast growth factor receptor 2 (FGFR2) fusion or another rearrangement as detected by an FDA-approved test. Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Infigratinib undergoes metabolic processing primarily in: According to _in vitro_ findings, about 94% of infigratinib is metabolized by CYP3A4 and about 6% of the drug is metabolized by flavin-containing monooxygenase 3 (FMO3). About 38% of the dose is circulating parent drug in the plasma and BHS697 and CQM157 are two major metabolites of infigratinib that are each found at >10% of the dose. They are pharmacologically active, with BHS697 representing about 16% to 33% of the overall pharmacological activity of infigratinib and CQM157 contributing to about 9% to 12%. BHS697 undergoes further metabolism mediated by CYP3A4 and CQM157 is metabolized through both Phase I and Phase II biotransformation pathways. The exact metabolic pathways and the structure of BHS697 and CQM157 are not fully characterized. This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Infigratinib are crucial for its therapeutic efficacy: Mean (%CV) C_max is 282.5 ng/mL (54%) and AUC_0-24h is 3780 ngxh/mL (59%) for infigratinib. Infigratinib C_max and AUC increase more than proportionally across the dose range of 5 to 150 mg and steady state is achieved within 15 days. At steady state, median time to achieve peak infigratinib plasma concentration (T_max) is six hours, with a range between two and seven hours. Mean (%CV) C_max is 42.1 ng/mL (65%) for BHS697 and 15.7 ng/mL (92%) for CQM157. Mean (%CV) AUC_0-24h is 717 ngxh/mL (55%) for BHS697 and 428 ngxh/mL (72%) for CQM157. In healthy subjects, a high-fat and high-calorie meal increased AUCinf of infigratinib by 80%-120% and C_max by 60%-80%. The median T_max also shifted from four hours to six hours. A low-fat low-calorie meal increased the mean AUC_inf of infigratinib by 70% and C_max by 90%/. The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Infigratinib is an important consideration for its dosing schedule: The geometric mean (CV%) terminal half-life of infigratinib was 33.5 h (39%) at steady state. This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Infigratinib exhibits a strong affinity for binding with plasma proteins: Infigratinib is about 96.8% bound to plasma proteins, primarily to lipoprotein. Protein binding is concentration-dependent. This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Infigratinib from the body primarily occurs through: Following administration of a single oral dose of radiolabeled infigratinib in healthy subjects, approximately 77% of the dose was recovered in feces, where 3.4% of the dose was in the unchanged parent form. About 7.2% was recovered in urine with 1.9% of the dose was unchanged. Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Infigratinib is distributed throughout the body with a volume of distribution of: At steady state, the geometric mean (CV%) apparent volume of distribution of infigratinib was 1600 L (33%). In rats receiving a single oral dose, infigratinib had brain-to-plasma concentration ratios (based on AUC_0-inf) of 0.682. This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Infigratinib is a critical factor in determining its safe and effective dosage: The geometric mean (CV%) total apparent clearance (CL/F) of infigratinib was 33.1 L/h (59%) at steady state. It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Infigratinib exerts its therapeutic effects through: Infigratinib is an anti-tumour agent that works to suppress tumour growth in cholangiocarcinoma. It exhibits anti-tumour activity in mouse and rat xenograft models of human tumours with activating FGFR2 or FGFR3 alterations, such as FGFR2-TTC28 or FGFR2-TRA2B fusions. In clinical trials, patients with cholangiocarcinoma who were treated with infigratinib had an overall response rate of 23% - where one patient had a complete response - and a duration of response of 5.5 months, with a range between 0.03 and 28.3 months. Some patients with cancers with FGFR mutations display intrinsic resistance to infigratinib, leading to negligible therapeutic efficacy: investigations are ongoing to target molecular pathways to combat drug resistance. The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Infigratinib functions by: Fibroblast growth factor receptors (FGFRs) are tyrosine kinase receptors that play a role in cell proliferation, differentiation, migration, survival, and angiogenesis. Upon binding of extracellular signals, primarily fibroblast growth factors, FGFR dimerizes to promote phosphorylation of downstream molecules and activation of the Ras-mitogen-activated protein kinase (MAPK) pathway. In some cancers, the FGFR signalling pathway is aberrant and disrupted, leading to unregulated cell proliferation and growth, including malignant cells. Alterations in the FGFR receptors, including mutations, amplifications, and fusions, are associated with a wide array of neoplasms, including prostate, urothelial, ovarian, breast, and liver cancer. In particular, FGFR2 fusion is closely related to intrahepatic cholangiocarcinoma: recent studies show that up to 45% of patients with intrahepatic cholangiocarcinoma exhibited gene rearrangements resulting in FGFR2 fusion proteins. Alterations in FGFR in tumours can lead to constitutive FGFR signalling, supporting the proliferation and survival of malignant cells. Infigratinib is a reversible, non-competitive inhibitor of all four FGFR subtypes - FGFR1, FGFR2, FGFR3, and FGFR4 - that blocks FGFR signalling and inhibits cell proliferation in cancer cell lines with activating FGFR amplification, mutations, or fusions. Out of the four FGFR subtypes, infigratinib has the highest affinity for FGFR1, FGFR2, and FGFR3. Infigratinib binds to the allosteric site between the two kinase lobes of the FGFR - or more specifically, to the ATP-binding cleft. Binding to this cleft prevents autophosphorylation of the receptor and blocks downstream signalling cascades that would otherwise activate MAPK. This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Classification:

Infigratinib belongs to the class of organic compounds known as phenylpiperazines. These are compounds containing a phenylpiperazine skeleton, which consists of a piperazine bound to a phenyl group, classified under the direct parent group Phenylpiperazines. This compound is a part of the Organic compounds, falling under the Organoheterocyclic compounds superclass, and categorized within the Diazinanes class, specifically within the Piperazines subclass.

Categories:

Infigratinib is categorized under the following therapeutic classes: Amides, Antineoplastic Agents, Antineoplastic and Immunomodulating Agents, BCRP/ABCG2 Inhibitors, BCRP/ABCG2 Substrates, Benzene Derivatives, BSEP/ABCB11 Inhibitors, Cytochrome P-450 CYP3A Substrates, Cytochrome P-450 CYP3A4 Substrates, Cytochrome P-450 CYP3A4 Substrates (strength unknown), Cytochrome P-450 Substrates, Fibroblast Growth Factor 2, antagonists & inhibitors, Fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitors, Kinase Inhibitor, MATE 1 Inhibitors, MATE 2 Inhibitors, MATE inhibitors, OATP1B1/SLCO1B1 Inhibitors, OATP1B3 inhibitors, OCT1 inhibitors, OCT2 Inhibitors, P-glycoprotein inhibitors, P-glycoprotein substrates, Protein Kinase Inhibitors, Receptor, Fibroblast Growth Factor, Type 1, antagonists & inhibitors, Receptors, Fibroblast Growth Factor, antagonists & inhibitors, Tyrosine Kinase Inhibitors. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.

Experimental Properties:

Further physical and chemical characteristics of Infigratinib include:

• Boiling Point: 747.9