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General Description:

Pralsetinib, identified by CAS number 2097132-94-8, is a notable compound with significant therapeutic applications. Pralsetinib, similar to the previously approved , 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, including non-small cell lung cancer. Although multikinase inhibitors, including , , , , and , have shown efficacy in RET-driven cancers, their lack of specificity is generally associated with substantial toxicity. Pralsetinib (BLU-667) and (LOXO-292) represent the first generation of specific RET RTK inhibitors for the treatment of RET-driven cancers. Although a phase 1/2 trial of pralsetinib termed ARROW (NCT03037385) is still ongoing, pralsetinib was granted accelerated FDA approval on September 4, 2020, for the treatment of metastatic RET-fusion positive non-small cell lung cancer. It is currently marketed under the brand name GAVRETO™ by Blueprint Medicines.

Indications:

This drug is primarily indicated for: Pralsetinib is indicated for the treatment of metastatic non-small cell lung cancer (NSCLC) in adult patients who are confirmed to possess a rearranged during transfection (RET) gene fusion, as determined by an FDA approved test. It is also indicated in adult and pediatric patients 12 years of age and older for the treatment of advanced or metastatic _RET_-mutant medullary thyroid cancer, and in this same population for the treatment of advanced or metastatic _RET_ fusion-positive thyroid cancer who require systemic therapy and for whom radioactive iodine is not appropriate. Pralsetinib is currently approved for this indication 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:

Pralsetinib undergoes metabolic processing primarily in: Pralsetinib is metabolized _in vitro_ primarily by CYP3A4 and to a lesser extent by CYP2D6 and CYP1A2. Pralsetinib given as a single oral dose of 310 mg in healthy volunteers led to the detection of metabolites from both oxidation (M453, M531, and M549b) and glucuronidation (M709), although these constituted less than 5% of the detected material. This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Pralsetinib are crucial for its therapeutic efficacy: Pralsetinib given at 400 mg once daily resulted in a mean steady-state C_max of 2830 ng/mL (coefficient of variation, CV, 52.5%) and AUC_0-24h of 43900 ng\*h/mL (CV 60.2%). The C_max and AUC of pralsetinib increased inconsistently with increasing doses between 60 and 600 mg once daily, with a median T_max across this range of between two and four hours. At 400 mg once daily, pralsetinib reached steady-state plasma concentration by three to five days. Pralsetinib absorption is affected by food. A single dose of 400 mg given with a high-fat meal (800 to 1000 calories with 50 to 60% of calories coming from fat) increased the mean C_max by 104% (95% CI 65-153%), mean AUC_0-∞ by 122% (95% CI 96-152%), and the median T_max from four to 8.5 hours. The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Pralsetinib is an important consideration for its dosing schedule: Pralsetinib has a plasma elimination half-life of 14.7 ± 6.5 hours following a single dose and 22.2 ± 13.5 hours following multiple doses. This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Pralsetinib exhibits a strong affinity for binding with plasma proteins: Pralsetinib is 97.1% bound to plasma proteins regardless of concentration. This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Pralsetinib from the body primarily occurs through: Pralsetinib is primarily eliminated through the fecal route (73%, 66% unchanged) with a small amount found in the urine (6%, 4.8% unchanged). Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Pralsetinib is distributed throughout the body with a volume of distribution of: Pralsetinib has a mean apparent volume of distribution of 228 L (CV 75%). This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Pralsetinib is a critical factor in determining its safe and effective dosage: Pralsetinib has a mean apparent steady-state oral clearance of 9.1 L/h (CV 60%). It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Pralsetinib exerts its therapeutic effects through: Pralsetinib exerts an anti-tumour effect through specific inhibition of the rearranged during transfection (RET) tyrosine kinase, including multiple distinct oncogenic RET fusions, mutated RET kinase domains harbouring gatekeeper mutations, and in RET kinases with a variety of activating single point mutations. Due to pralsetinib's high selectivity for RET over other kinases, both _in vitro_ and _in vivo_, pralsetinib has been described as having a better safety profile compared to previously used multi-kinase inhibitors. Despite this, pralsetinib use may increase the risk of hypertension, hemorrhagic events, impaired wound healing, hepatotoxicity, interstitial lung disease/pneumonitis, and embryo-fetal toxicity. The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Pralsetinib 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 achieved through chromosomal rearrangements producing 5' fusions of dimerizable domains to the 3' _RET_ tyrosine kinase domain leading to constitutive dimerization and subsequent autophosphorylation; the most common fusions are _KIF5B-RET_ and _CCDC6-RET_, although more than 35 genes have been reported to fuse with _RET_. Constitutive activation leads to increased downstream signalling and is associated with tumour invasion, migration, and proliferation. Pralsetinib (formerly referred to as BLU-667) was developed through screening more than 10,000 agnostically designed kinase inhibitors followed by extensive chemical modification to improve its properties. Pralsetinib displays _in vitro_ IC₅₀ values for both WT RET as well as several mutant forms, including CCDC6-RET, in the range of 0.3-0.4 nmol/L, and is 100-fold more selective for RET kinase over 96% of 371 kinases tested. It is this specific inhibition of RET kinase that is associated with anti-tumour activity and clinical benefit in patients. Despite increased selectivity for RET over other kinases, pralsetinib has been reported to inhibit DDR1, TRKC, FLT3, JAK1-2, TRKA, VEGFR2, PDGFRb, and FGFR1-2 at clinically relevant concentrations. The significance of these findings remains uncertain. This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Categories:

Pralsetinib is categorized under the following therapeutic classes: Antineoplastic Agents, Antineoplastic and Immunomodulating Agents, BCRP/ABCG2 Inhibitors, BCRP/ABCG2 Substrates, BSEP/ABCB11 Inhibitors, Cytochrome P-450 CYP1A2 Substrates, Cytochrome P-450 CYP2C8 Inducers, Cytochrome P-450 CYP2C8 Inducers (strength unknown), Cytochrome P-450 CYP2C8 Inhibitors, Cytochrome P-450 CYP2C8 Inhibitors (strength unknown), Cytochrome P-450 CYP2C9 Inducers, Cytochrome P-450 CYP2C9 Inducers (strength unknown), Cytochrome P-450 CYP2C9 Inhibitors, Cytochrome P-450 CYP2C9 Inhibitors (strength unknown), Cytochrome P-450 CYP2D6 Substrates, Cytochrome P-450 CYP3A Inducers, Cytochrome P-450 CYP3A Inhibitors, Cytochrome P-450 CYP3A Substrates, Cytochrome P-450 CYP3A4 Inducers, Cytochrome P-450 CYP3A4 Inducers (strength unknown), Cytochrome P-450 CYP3A4 Inhibitors, Cytochrome P-450 CYP3A4 Inhibitors (strength unknown), Cytochrome P-450 CYP3A4 Substrates, Cytochrome P-450 CYP3A5 Inducers, Cytochrome P-450 CYP3A5 Inducers (strength unknown), Cytochrome P-450 CYP3A5 Inhibitors, Cytochrome P-450 CYP3A5 Inhibitors (strength unknown), Cytochrome P-450 Enzyme Inducers, Cytochrome P-450 Enzyme Inhibitors, Cytochrome P-450 Substrates, Kinase Inhibitor, MATE 1 Inhibitors, MATE 2 Inhibitors, MATE inhibitors, OAT1/SLC22A6 inhibitors, OATP1B1/SLCO1B1 Inhibitors, OATP1B3 inhibitors, P-glycoprotein inhibitors, P-glycoprotein substrates, Protein Kinase Inhibitors, Rearranged during Transfection (RET) 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 Pralsetinib include:

• Water Solubility:<0.1 mg/ml