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General Description:

Pexidartinib, identified by CAS number 1029044-16-3, is a notable compound with significant therapeutic applications. Pexidartinib is a selective tyrosine kinase inhibitor that works by inhibiting the colony-stimulating factor (CSF1)/CSF1 receptor pathway. Pexidartinib was originally developed by Daiichi Sankyo, Inc. and it was approved by the FDA in August 2019 as the first systemic therapy for adult patients with symptomatic tenosynovial giant cell tumor. Tenosynovial giant cell tumor is a rare form of non-malignant tumor that causes the synovium and tendon sheaths to thicken and overgrow, leading to damage in surrounding joint tissue. Debilitating symptoms often follow with tenosynovial giant cell tumors, along with a risk of significant functional limitations and a reduced quality of life in patients. While surgical resection is a current standard of care for tenosynovial giant cell tumor, there are tumor types where surgeries are deemed clinically ineffective with a high risk of lifetime recurrence. Pexidartinib works by blocking the immune responses that are activated in tenosynovial giant cell tumors. In clinical trials, pexidartinib was shown to promote improvements in patient symptoms and functional outcomes in TGCT. Pexidartinib is available in oral formulations and it is commonly marketed as Turalio.

Indications:

This drug is primarily indicated for: Pexidartinib is indicated for the treatment of adult patients with symptomatic tenosynovial giant cell tumor (TGCT) associated with severe morbidity or functional limitations and not amenable to improvement with surgery. Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Pexidartinib undergoes metabolic processing primarily in: Pexidartinib primarily undergoes oxidation mediated by hepatic CYP3A4 and glucuronidation by UGT1A4. Following UGT1A4-mediated glucuronidation, a major inactive N-glucuronide metabolite is formed with approximately 10% higher exposure than the parent drug after a single dose administration of pexidartinib. Based on the findings of _in vitro_ studies, CYP1A2 and CYP2C9 may also play a minor role in drug metabolism. This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Pexidartinib are crucial for its therapeutic efficacy: Following administration of single doses in healthy subjects and multiple doses in patients, the mean Cmax was 8625 ng/mL and the mean AUC was 77465 ngxh/mL. The median Tmax was 2.5 hours and the time to reach the steady state was approximately 7 days. Administration of pexidartinib with a high fat meal resulted in an increased drug Cmax and AUC by 100%, with a delay in Tmax by 2.5 hours. The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Pexidartinib is an important consideration for its dosing schedule: The elimination half-life is about 26.6 hours. This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Pexidartinib exhibits a strong affinity for binding with plasma proteins: Based on the findings of _in vitro_ plasma protein binding study, pexidartinib is about 99% bound to serum proteins, where it is extensively bound to human serum albumin by 99.9% and alpha-1-acid glycoprotein by 89.9%. This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Pexidartinib from the body primarily occurs through: Pexidartinib is predominantly excreted via feces, where fecal excretion accounts for 65% of total pexidartinib elimination. Via this route of elimination, about 44% of the compound found in feces is recovered as unchanged parent drug. The renal elimination accounts for 27% of pexidartinib elimination, where more than 10% of the compound is found as the N-glucuronide metabolite. Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Pexidartinib is distributed throughout the body with a volume of distribution of: The apparent volume of distribution of pexidartinib is about 187 L. In rats, pexidartinib was shown to penetrate into the central nervous system. This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Pexidartinib is a critical factor in determining its safe and effective dosage: The apparent clearance is about 5.1 L/h. It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Pexidartinib exerts its therapeutic effects through: Pexidartinib works by suppressing the growth of tenosynovial giant cell tumors. In clinical trials comprising of patients with symptomatic tenosynovial giant cell tumor, pexidartinib had a higher overall response rate, characterized by improved patient symptoms and functional outcomes, compared to placebo. Pexidartinib works by inhibiting the activation and signaling of tumor-permissive cytokines and receptor tyrosine kinases that play a central role in tumor cell proliferation and survival. Taking pexidartinib with a high-fat meal may increase the incidence and severity of adverse reactions, including hepatotoxicity. The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Pexidartinib functions by: Tenosynovial giant cell tumor is a rare, non-malignant neoplasm that causes abnormal growth and damage to the synovium, bursae, or tendon sheaths. Recruitment of immune cells, specifically macrophages, is closely associated with the tumor mass formation in tenosynovial giant cell tumors. Macrophages drive tumor-promoting inflammation and play a central role in every stage of tumor progression. As the most abundant immune cells in the tumor microenvironment of solid tumors, macrophages promote processes that enhance tumor survival, such as angiogenesis, tumor cell invasion, and intravasation at the primary site. They also modulate the immune response to tumors to inhibit tumor clearance and directly engage with tumor cells to activate pro-survival signaling pathways. The recruitment, proliferation, and irreversible differentiation of macrophages are regulated by colony-stimulating factor-1 (CSF-1), which is a cytokine that is often translocated and highly expressed in tenosynovial giant cell tumors. Elevated expression of CSF-1 and CSF-1 receptor (CSF1R) has also been implicated in various models of malignant cancers and tumors. Pexidartinib targets the CSF1/CSF1R pathway as a selective CSF1R inhibitor. It stimulates the autoinhibited state of the CSF1R by interacting with the juxtamembrane region of CSF1R, which is responsible for folding and inactivation of the kinase domain, and preventing the binding of CSF1 and ATP to the region. Without the binding of CSF1 to the receptor, CSF1R cannot undergo ligand-induced autophosphorylation. By inhibiting the CSF1R signaling pathway, pexidartinib works to inhibit tumor cell proliferation and downmodulate cells involved in the disease, such as macrophages. It was also shown to inhibit the CD117 or proto-oncogene receptor tyrosine kinase (cKIT), mutant fms-like tyrosine kinase 3 (FLT3), and platelet-derived growth factor receptor (PDGFR)-β, which are all receptor tyrosine kinases that regulate critical cellular processes such as cell proliferation and survival. This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Classification:

Pexidartinib belongs to the class of organic compounds known as pyrrolopyridines. These are compounds containing a pyrrolopyridine moiety, which consists of a pyrrole ring fused to a pyridine. Pyrrole is 5-membered ring consisting of four carbon atoms and one nitrogen atom. Pyridine is a 6-membered ring consisting of five carbon atoms and one nitrogen center, classified under the direct parent group Pyrrolopyridines. This compound is a part of the Organic compounds, falling under the Organoheterocyclic compounds superclass, and categorized within the Pyrrolopyridines class, specifically within the None subclass.

Categories:

Pexidartinib is categorized under the following therapeutic classes: Amines, Antineoplastic Agents, Antineoplastic and Immunomodulating Agents, Cancer immunotherapy, 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 CYP2C9 Inhibitors, Cytochrome P-450 CYP2C9 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 (weak), Cytochrome P-450 CYP3A4 Inhibitors, Cytochrome P-450 CYP3A4 Inhibitors (weak), Cytochrome P-450 CYP3A4 Substrates, Cytochrome P-450 CYP3A4 Substrates with a Narrow Therapeutic Index, Cytochrome P-450 Enzyme Inducers, Cytochrome P-450 Enzyme Inhibitors, Cytochrome P-450 Substrates, Hepatotoxic Agents, Immunotherapy, Kinase Inhibitor, MATE 1 Inhibitors, MATE 2 Inhibitors, MATE inhibitors, Narrow Therapeutic Index Drugs, OATP1B1/SLCO1B1 Inhibitors, OATP1B3 inhibitors, Organic Anion Transporting Polypeptide 2B1 Inhibitors, Protein Kinase Inhibitors, Pyridines, Tyrosine Kinase Inhibitors, UGT1A1 Inhibitors, UGT1A4 substrates. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.