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General Description:

Selpercatinib, identified by CAS number 2152628-33-4, is a notable compound with significant therapeutic applications. Selpercatinib is a kinase inhibitor with enhanced specificity for RET tyrosine kinase receptors (RTKs) over other RTK classes. Enhanced RET (Rearranged during transfection) oncogene expression is a hallmark of many cancers. Although multikinase inhibitors, including , , , , and , have shown efficacy in RET-driven cancers, their lack of specificity is generally associated with substantial toxicity. Selpercatinib (LOXO-292) and pralsetinib (BLU-667) represent the first generation of specific RET RTK inhibitors for the treatment of RET-driven cancers. Although selpercatinib is currently still under investigation in clinical trial NCT04211337, it was granted accelerated FDA approval on May 8, 2020, for specific RET-driven cancer indications. It is currently marketed under the brand name RETEVMO™ by Loxo Oncology Inc. Selpercatinib is also approved by the European Commission.

Indications:

This drug is primarily indicated for: Selpercatinib is approved to treat: - adult with locally advanced or metastatic non-small cell lung cancer (NSCLC) with a rearranged during transfection (RET) gene fusion. In Europe, patients should require systemic therapy following prior treatment with immunotherapy and/or platinum-based chemotherapy. - adults and children 12 years of age and older with advanced or metastatic medullary thyroid cancer (MTC) with a RET mutation who require systemic therapy In Europe, patients should have been previously treated with and/or . - adults and children 12 years and older with advanced RET-mutant medullary thyroid cancer (MTC) who require systemic therapy following prior treatment with and/or - adults and children 12 years of age and older with advanced or metastatic thyroid cancer with a RET gene fusion who require systemic therapy and who are radioactive iodine-refractory (if radioactive iodine is appropriate) - adults with locally advanced or metastatic solid tumors with a RET gene fusion that have progressed on or following prior systemic treatment or who have no satisfactory alternative treatment options Selpercatinib is currently approved for these indications under an accelerated approval scheme and continued approval may be contingent on future confirmatory trials. Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Selpercatinib undergoes metabolic processing primarily in: Selpercatinib is predominantly metabolized in the liver by CYP3A4. This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Selpercatinib are crucial for its therapeutic efficacy: In patients with locally advanced or metastatic solid tumours receiving 160 mg of selpercatinib twice daily, steady-state was achieved after approximately 7 days, with a C_max of 2,980 (CV 53%) and AUC_0-24h of 51,600 (CV 58%). The absolute bioavailability is between 60 and 82% (mean 73%), and the median t_max is two hours. Food has no apparent effect on the AUC or C_max of selpercatinib. Patients with hepatic impairment display a concomitant increase in AUC_0-INF for mild (7%), moderate (32%), and severe (77%) impairment. The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Selpercatinib is an important consideration for its dosing schedule: Selpercatinib has a half-life of 32 hours in healthy individuals. This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Selpercatinib exhibits a strong affinity for binding with plasma proteins: Selpercatinib displays 97% _in vitro_ protein binding independent of concentration and a blood-plasma concentration ratio of 0.7. This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Selpercatinib from the body primarily occurs through: Selpercatinib administered as a single 160 mg dose in healthy individuals was primarily recovered in feces (69%, 14% unchanged) and urine (24%, 12% unchanged). Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Selpercatinib is distributed throughout the body with a volume of distribution of: Selpercatinib has an apparent volume of distribution of 191 L; the volume of distribution increases with increasing body weight. This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Selpercatinib is a critical factor in determining its safe and effective dosage: Selpercatinib has an apparent clearance of 6L/h; the clearance increases with increasing body weight. It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Selpercatinib exerts its therapeutic effects through: Selpercatinib exerts anti-tumour activity in specific cancers through inhibition of mutated forms of RET tyrosine kinases. Due to its increased specificity for RET over other tyrosine kinases, selpercatinib is thought to have an improved safety profile compared to other multi-kinase inhibitors. Despite this, selpercatinib treatment is associated with hepatotoxicity, hypertension, QT interval prolongation, hemorrhagic events, risk of impaired wound healing, and embryo-fetal toxicity; some patients may also exhibit hypersensitivity to selpercatinib. The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Selpercatinib functions by: Rearranged during transfection (RET) is a transmembrane receptor tyrosine kinase containing extracellular, transmembrane, and intracellular domains whose activity is required for normal kidney and nervous system development. Constitutive RET activation is primarily achieved through chromosomal rearrangements producing 5' fusions of dimerizable domains to the 3' _RET_ tyrosine kinase domain, such as _KIF5B-RET_ and _CCDC6-RET_, resulting in constitutive dimerization and subsequent autophosphorylation. Constitutive activation leads to increased downstream signalling and is associated with tumour invasion, migration, and proliferation. Selpercatinib is a direct RET kinase inhibitor, exhibiting IC₅₀ values between 0.92 and 67.8 nM depending on the exact _RET_ genotype. Information based on natural as well as induced resistance mutations and molecular modelling suggests that selpercatinib directly inhibits RET autophosphorylation by competing with ATP for binding. Various single amino acid mutations at position 810 inhibit selpercatinib binding without significantly altering ATP binding, potentially leading to treatment failures. Selpercatinib is also reported to inhibit other tyrosine kinase receptors, including VEGFR1, VEGFR3, FGFR1, FGFR2, and FGFR3, at clinically relevant concentrations. The significance of these effects is not well studied. This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Categories:

Selpercatinib is categorized under the following therapeutic classes: Agents that produce hypertension, Antineoplastic Agents, Antineoplastic and Immunomodulating Agents, BCRP/ABCG2 Inhibitors, BCRP/ABCG2 Substrates, Cytochrome P-450 CYP2C8 Inhibitors, Cytochrome P-450 CYP2C8 Inhibitors (strength unknown), Cytochrome P-450 CYP3A Inhibitors, Cytochrome P-450 CYP3A Substrates, Cytochrome P-450 CYP3A4 Substrates, Cytochrome P-450 Enzyme Inhibitors, Cytochrome P-450 Substrates, Hepatotoxic Agents, Kinase Inhibitor, MATE 1 Inhibitors, MATE inhibitors, P-glycoprotein inhibitors, P-glycoprotein substrates, Protein Kinase Inhibitors, QTc Prolonging Agents, Rearranged during Transfection (RET) 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 Selpercatinib include:

• Water Solubility:<1 mg/mL