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Mobocertinib API Manufacturers & Suppliers

General Description:

Mobocertinib, identified by CAS number 1847461-43-1, is a notable compound with significant therapeutic applications. Mobocertinib is a kinase inhibitor targeted against human epidermal growth factor receptor (EGFR). It is used specifically in the treatment of non-small cell lung cancer (NSCLC) caused by exon 20 insertion mutations in the _EGFR_ gene, which are typically associated with a poorer prognosis (as compared to "classical" _EGFR_ mutants causing NSCLC) and are associated with resistance to standard targeted EGFR inhibitors. Mobocertinib appears to be an effective means of treating this otherwise treatment-resistant NSCLC, exerting an inhibitory effect on _EGFR_ exon 20 insertion mutant variants at concentrations 1.5- to 10-fold lower than those required to inhibit wild-type EGFR. Mobocertinib, under the brand name Exkivity (Takeda Pharmaceuticals Inc.), was granted accelerated approval by the FDA in September 2021 for the treatment of locally advanced or metastatic NSCLC in patients with _EGFR_ exon 20 insertion mutations who have failed previous therapies.

Indications:

This drug is primarily indicated for: Mobocertinib is indicated for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion mutations whose disease has progressed on or after platinum-based chemotherapy. Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Mobocertinib undergoes metabolic processing primarily in: Mobocertinib is metabolized primarily by CYP3A enzymes to two active metabolites, AP32960 and AP32914, which are equipotent to mobocertinib and account for 36% and 4% of its combined molar AUC, respectively. This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Mobocertinib are crucial for its therapeutic efficacy: The mean absolute bioavailability of mobocertinib is 37% and the median T_max is approximately 4 hours. Following a single oral dose of 160mg of mobocertinib to fasted patients, the mean C_max and AUC_0-inf were 45.8 ng/mL and 862 ng•h/mL, respectively. The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Mobocertinib is an important consideration for its dosing schedule: At steady-state, the mean elimination half-life of mobocertinib and its two active metabolites, AP32960 and AP32914, was 18 hours, 24 hours, and 18 hours, respectively. This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Mobocertinib exhibits a strong affinity for binding with plasma proteins: Mobocertinib and its metabolites are extensively protein-bound in plasma, although the specific proteins to which they bind have not been elucidated. Following oral administration, mobocertinib is 99.3% protein-bound, AP32960 is 99.5% protein-bound, and AP32914 is 98.6% protein-bound. This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Mobocertinib from the body primarily occurs through: Following oral administration of mobocertinib, approximately 76% of the administered dose was recovered in the feces (6% as unchanged parent drug) with only 4% recovered in the urine (1% as unchanged parent drug). The metabolite AP32960 comprised 12% and 1% of the recovered dose found in the feces and urine, respectively, while the metabolite AP32914 was below the detection limit in both. Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Mobocertinib is distributed throughout the body with a volume of distribution of: The mean apparent volume of distribution of mobocertinib was approximately 3,509 L at steady-state. This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Mobocertinib is a critical factor in determining its safe and effective dosage: At steady-state, the mean apparent oral clearance of mobocertinib and its two active metabolites, AP32960 and AP32914, was 138 L/hr, 149 L/hr, and 159 L/hr, respectively. It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Mobocertinib exerts its therapeutic effects through: Mobocertinib is an inhibitor of EGFR that preferentially targets exon 20 insertion mutant variants. It is available as an oral capsule taken with or without food once daily. Mobocertinib can cause a concentration-dependent increase in QTc interval which may lead to life-threatening complications such as Torsades de Pointes. Patients with baseline risk factors for QTc prolongation should consider alternative medications or be monitored carefully throughout therapy. The use of concomitant QTc-prolonging medications should be avoided, as should concomitant inhibitors of CYP3A, as these may increase the concentration of mobocertinib and thus the risk of QTc-prolongation. The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Mobocertinib functions by: The epidermal growth factor receptor (EGFR) is a transmembrane receptor that regulates signaling pathways in the control of cellular proliferation. Mutations in these proteins have been associated with certain types of lung cancer, including non-small cell lung cancer (NSCLC). While the majority of _EGFR_ mutations associated with NSCLC involve the _EGFR_ L858R point mutation or exon 19 deletions (referred to as "classical" _EGFR_ mutations), less common _EGFR_ exon 20 insertion mutations carry a particularly poor prognosis and are associated with resistance to standard targeted EGFR inhibitors. Mobocertinib is an inhibitor of EGFR that irreversibly binds to and inhibits EGFR exon 20 insertion mutations at lower concentrations than wild-type EGFR proteins, exerting a pharmacologic effect on mutant variants at concentrations 1.5- to 10-fold lower than on wild-type proteins. This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Categories:

Mobocertinib is categorized under the following therapeutic classes: BCRP/ABCG2 Inhibitors, Cytochrome P-450 CYP3A Substrates, Cytochrome P-450 CYP3A4 Substrates, Cytochrome P-450 CYP3A5 Substrates, Cytochrome P-450 CYP3A7 Substrates, Cytochrome P-450 Substrates, Kinase Inhibitor, P-glycoprotein inhibitors, P-glycoprotein substrates, QTc Prolonging Agents. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.

Experimental Properties:

Further physical and chemical characteristics of Mobocertinib include:

• Water Solubility: 152 mg/mL @ pH 1.0; >17.6 mg/mL @ pH 6.8