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General Description:

Pirtobrutinib, identified by CAS number 2101700-15-4, is a notable compound with significant therapeutic applications. Pirtobrutinib is a small molecule and a highly selective non-covalent inhibitor of Bruton’s tyrosine kinase (BTK). Its high selectivity has been associated with lower discontinuation rates due to adverse events and a lower incidence of atrial fibrillation. Unlike BTK covalent inhibitors, such as , that bind to the cysteine 481 (Cys481) amino acid within the active site of BTK, the inhibitory activity of pirtobrutinib is maintained even in the presence of Cys481 mutations. Although the mechanisms of resistance to covalent BTK inhibitors have not been fully elucidated, it appears that the presence of Cys481 mutations is the most common reason for resistance to covalent BTK inhibitors. However, other mutations may confer resistance to non-covalent BTK inhibitors such as pirtobrutinib. In January 2023, the use of pirtobrutinib for the treatment of relapsed or refractory mantle cell lymphoma (MCL) after at least two lines of systemic therapy was approved under the FDA's Accelerated Approval pathway.

Indications:

This drug is primarily indicated for: Pirtobrutinib is indicated for the treatment of adult patients with relapsed or refractory mantle cell lymphoma (MCL) after at least two lines of systemic therapy, including a BTK inhibitor. Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Pirtobrutinib undergoes metabolic processing primarily in: In vitro studies suggest that pirtobrutinib is mainly metabolized by CYP3A4 and direct glucuronidation by UGT1A8 and UGT1A9. This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Pirtobrutinib are crucial for its therapeutic efficacy: With single oral doses between 300 mg and 800 mg (1.5 to 4 times the approved recommended dose) and once daily doses between 25 mg and 300 mg (0.125 to 1.5 times the recommended dose), pirtobrutinib follows a dose-proportional pharmacokinetic profile. Within 5 days of once-daily dosing, pirtobrutinib reached steady-state concentration, with an accumulation ratio of 1.63 based on AUC after 200 mg dosages. With the recommended dose, pirtobrutinib has a steady-state AUC and C_max of 91300 h⋅ng/mL and 6460 ng/mL, respectively. On day 8 of cycle 1, pirtobrutinib had an AUC_0-24 of 81800 h⋅ng/mL and a C_max of 3670 ng/mL. After approximately 2 hours, pirtobrutinib reaches peak plasma concentration (t_max). After a single oral dose of 200 mg, pirtobrutinib reaches an absolute bioavailability of 85.5%. The administration of a high-fat, high-calorie meal to healthy subjects did not have a clinically significant effect on the pharmacokinetics of pirtobrutinib. A high-fat meal decreased the C_max of pirtobrutinib by 23%, delayed t_max by 1 hour and had no effects on the AUC. The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Pirtobrutinib is an important consideration for its dosing schedule: Pirtobrutinib has an effective half-life of approximately 19 hours. This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Pirtobrutinib exhibits a strong affinity for binding with plasma proteins: The human protein binding of pirtobrutinib is 96%, independent of _in vitro_ concentration. Pirtobrutinib has a blood-to-plasma ratio of 0.79. This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Pirtobrutinib from the body primarily occurs through: Pirtobrutinib is mainly excreted in urine and feces. In healthy subjects given a single dose of 200 mg of radiolabeled pirtobrutinib, 57% of the dose was recovered in urine (10% unchanged), and 37% was recovered in feces (18% unchanged). Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Pirtobrutinib is distributed throughout the body with a volume of distribution of: Pirtobrutinib has an apparent central volume of distribution of 32.8 L. This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Pirtobrutinib is a critical factor in determining its safe and effective dosage: Pirtobrutinib has an apparent clearance of 2.02 L/h. It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Pirtobrutinib exerts its therapeutic effects through: Pirtobrutinib is a non-covalent inhibitor of Bruton’s tyrosine kinase (BTK) with more than 300-fold selectivity for BTK over 98% of other kinases. _In vivo_ murine studies suggest that pirtobrutinib has an efficacy similar to ibrutinib with BTK wild-type tumor cells but an improved efficacy in BTK Cys481 mutant cells. Pirtobrutinib has shown efficacy against different B-cell malignancies and is effective in patients that are intolerant of irreversible BTK inhibitors or have developed a disease resistant to these covalent inhibitors. At the recommended dosage of 200 mg once daily, pirtobrutinib trough concentrations exceeded the BTK IC₉₆. In healthy subjects given a single 900 mg dose (concentration 2 times higher than the steady state at the recommended dosage), pirtobrutinib did not have a clinically meaningful effect on the change in QTcF interval, and there was no relationship between pirtobrutinib exposure and change in QTc interval. The use of pirtobrutinib may lead to fatal and serious infections, hemorrhage, cytopenias, atrial fibrillation and atrial flutter. Patients should also be warned about the development of second primary malignancies. The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Pirtobrutinib functions by: Bruton’s tyrosine kinase (BTK) is a tyrosine kinase located in the cytoplasm that is recruited to the cytoplasm upon activation. In B-cells, BTK participates in the activation of B-cell antigen receptor (BCR) signaling and cytokine receptor pathways, both critical for B-cell development, function, adhesion and migration. Therefore, the inhibition of BTK is a valuable target for the treatment of B-cell cancers. Pirtobrutinib binds to Bruton’s tyrosine kinase (BTK) in a non-covalent manner and inhibits its activity. Unlike other BTK inhibitors that bind covalently to the active site of BTK, the inhibitory activity of pirtobrutinib is maintained even in the presence of mutations in this region, such as the presence of Cys481. In nonclinical studies, pirtobrutinib inhibited BTK-mediated B-cell CD69 expression and inhibited malignant B-cell proliferation. This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Categories:

Pirtobrutinib is categorized under the following therapeutic classes: Antineoplastic Agents, Antineoplastic and Immunomodulating Agents, BCRP/ABCG2 Inhibitors, BCRP/ABCG2 Substrates, Bruton's tyrosine kinase (BTK) inhibitors, Cancer immunotherapy, Cytochrome P-450 CYP1A2 Inhibitors, Cytochrome P-450 CYP1A2 Inhibitors (strength unknown), Cytochrome P-450 CYP2B6 Inducers, Cytochrome P-450 CYP2B6 Inducers (strength unknown), Cytochrome P-450 CYP2B6 Inhibitors, Cytochrome P-450 CYP2B6 Inhibitors (strength unknown), Cytochrome P-450 CYP2C19 Inducers, Cytochrome P-450 CYP2C19 Inducers (strength unknown), Cytochrome P-450 CYP2C19 Inhibitors, Cytochrome P-450 CYP2C19 Inhibitors (weak), Cytochrome P-450 CYP2C8 Inhibitors, Cytochrome P-450 CYP2C8 Inhibitors (moderate), Cytochrome P-450 CYP2C9 Inhibitors, Cytochrome P-450 CYP2C9 Inhibitors (strength unknown), Cytochrome P-450 CYP2D6 Inhibitors, Cytochrome P-450 CYP2D6 Inhibitors (strength unknown), 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 (weak), Cytochrome P-450 CYP3A4 Substrates, Cytochrome P-450 CYP3A5 Inducers, Cytochrome P-450 CYP3A5 Inducers (strength unknown), Cytochrome P-450 Enzyme Inducers, Cytochrome P-450 Enzyme Inhibitors, Cytochrome P-450 Substrates, Enzyme Inhibitors, Immunosuppressive Agents, Immunotherapy, Kinase Inhibitor, Myelosuppressive Agents, P-glycoprotein inhibitors, P-glycoprotein substrates, Protein Kinase Inhibitors, Tyrosine Kinase Inhibitors, UGT1A9 Substrates. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.

Experimental Properties:

Further physical and chemical characteristics of Pirtobrutinib include:

• Water Solubility: Practically insoluble or insoluble