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General Description:

Pemigatinib, identified by CAS number 1513857-77-6, is a notable compound with significant therapeutic applications. Pemigatinib is a small molecule kinase inhibitor with antitumour activity. It works by inhibiting fibroblast growth factor receptors (FGFRs), which are receptor tyrosine kinases that activate signalling pathways in tumour cells. FGFRs gained attention as potential therapeutic targets in selected cancers, as FGFR gene alterations were observed in a wide variety of cancers including those of the urinary bladder, breast, ovary, prostate, endometrium, lung, and stomach. Deregulated FGFR signalling pathway can lead the development of oncogenes and tumour-promoting physiological processes, such as cancer cell proliferation, enhanced angiogenesis, and evasion of cell death. In April 2020, pemigatinib was approved by the FDA for the treatment of unresectable locally advanced or metastatic cholangiocarcinoma in previously treated adult patients with a fibroblast growth factor receptor 2 (FGFR2) gene fusion or other rearrangements as detected by an FDA-approved test. Cholangiocarcinoma is the most common primary malignancy affecting the biliary tract and the second most common primary hepatic malignancy. This malignancy accounts for 15% to 20% of primary hepatobiliary malignancies, which account for 13% of overall cancer-related global mortality. With increasing research on the pathogenesis of cholangiocarcinoma and potential therapeutic targets for anticancer drug treatment, recent studies show that up to 45% of patients with intrahepatic cholangiocarcinoma exhibited gene rearrangements resulting in oncogenic fibroblast growth factor 2 (FGFR2) fusion proteins. The FDA-approved indication for pemigatinib was granted under accelerated approval based on the overall response rate and duration of response in pre-marketing clinical trials. Pemigatinib is marketed under the brand name Pemazyre, and it is available as oral tablets.

Indications:

This drug is primarily indicated for: Pemigatinib is indicated for the treatment of unresectable locally advanced or metastatic cholangiocarcinoma in previously-treated adult patients with a fibroblast growth factor receptor 2 (FGFR2) fusion or other rearrangement as detected by an FDA-approved test. It is also indicated for the treatment of adults with relapsed or refractory myeloid/lymphoid neoplasms (MLNs) with FGFR1 rearrangement. Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Pemigatinib undergoes metabolic processing primarily in: Pemigatinib is predominantly metabolized by the CYP3A4 enzyme _in vitro_. Its specific metabolic pathway and resulting metabolites have not yet been characterized. This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Pemigatinib are crucial for its therapeutic efficacy: Following administration of a single oral dose of 13.5 mg pemigatinib, the median Tmax was 1.13 (0.50-6.00) hours. The steady state was reached within 4 days following repeated once daily dosing, with the median drug accumulation ratio of 1.63 (range 0.63 to 3.28). Steady-state concentration of pemigatinib increased in a dose-proportional manner over the dose range of 1 to 20 mg, which is about 0.07 to 1.5 times the recommended dose. The mean steady-state AUC and Cmax were 2620 nM x h (54% CV) and 236 nM, respectively. The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Pemigatinib is an important consideration for its dosing schedule: Following administration of a single oral dose of 13.5 mg pemigatinib, the geometric mean elimination half-life (t½) of pemigatinib was 15.4 (51.6% CV) hours. This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Pemigatinib exhibits a strong affinity for binding with plasma proteins: The _in vitro_ serum protein binding of pemigatinib was 90.6% at drug concentrations ranging from 1 to 10 µM. This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Pemigatinib from the body primarily occurs through: Following oral administration of a single radiolabeled dose of 11 mg pemigatinib, about 82.4% of the dose was recovered in feces. Of this recovered drug, about 1.4% of the dose was unchanged parent compound. About 12.6% of the dose was recovered in urine, where 1% of the dose was unchanged. Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Pemigatinib is distributed throughout the body with a volume of distribution of: The apparent volume of distribution was 235 L (60.8% CV) following a single oral dose of 13.5 mg pemigatinib. This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Pemigatinib is a critical factor in determining its safe and effective dosage: Following administration of a single oral dose of 13.5 mg pemigatinib, the geometric mean apparent clearance (CL/F) was 10.6 L/h (54% CV). It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Pemigatinib exerts its therapeutic effects through: Pemigatinib is a small molecule kinase inhibitor that exerts anti-tumour activity through inhibition of fibroblast growth factor receptors (FGFRs). With an IC₅₀ of less than 2 nM, pemigatinib displays potent inhibition of FGFR1, FGFR2, and FGFR3. In mouse xenograft models of human tumours with FGFR1, FGFR2, or FGFR3 alterations, pemigatinib exhibited potent anti-tumour activity by suppressing the growth of xenografted tumour models. It also showed efficacy against a patient-derived xenograft model of cholangiocarcinoma that expressed an oncogenic FGFR2­ Transformer-2 beta homolog (TRA2b) fusion protein. Pemigatinib also inhibited FGFR4 _in vitro_, however at a concentration approximately 100 times higher than those that inhibit FGFR1, 2, and 3. The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Pemigatinib functions by: Fibroblast growth factor receptor (FGFR) is a receptor tyrosine kinase involved in activating signalling pathways that promote cell proliferation, survival, and migration, as well as growth arrest and cellular differentiation. The initiation of the FGFR signalling pathway requires the binding of its natural ligand, fibroblast growth factor (FGF). Once FGF binds to the extracellular ligand-binding domain of the receptor, FGFRs dimerize and autophosphorylate the tyrosine residue in the intracellular tyrosine-kinase domain, leading to the activation of the tyrosine kinase. Downstream cascades involve phosphorylation of multiple intracellular signalling proteins, such as phosphatidylinositol 3 kinase (PI3K)-AKT and RAS/mitogen-activated protein kinase (MAPK), and phospholipase Cγ, which activates the protein kinase C pathway. FGFR-mediated pathway ultimately promotes cell growth, differentiation, survival, angiogenesis, and organogenesis, depending on cell type. Expressed in different isoforms in various tissues and cell lines, FGFRs are not constitutively active in normal cells. However, FGFR1, FGFR2, or FGFR3 alterations in certain tumours can lead to constitutive FGFR activation and aberrant FGFR signalling, supporting the proliferation and survival of malignant cells. Pemigatinib inhibits FGFR1, FGFR2, and FGFR3, blocking their signalling pathways and decreasing cell viability in cancer cell lines with activating FGFR amplification and fusions that resulted in constitutive activation of FGFR signalling. Genetic alterations in FGFR1, FGFR2, and FGFR3 (such as amplification, missense, or fusion mutations in the coding region) leading to constitutive activation of FGFR signalling pathways are observed in various tumours. However, alterations in FGFR genes are demonstrated in selected patients and do not always imply oncogene development. Therefore, it is imperative that fusion or rearrangement of FGFRs are demonstrated through tests prior to initiation of drug therapy. This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Categories:

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