Capmatinib API Manufacturers

General Description:

Capmatinib, identified by CAS number 1029712-80-8, is a notable compound with significant therapeutic applications. Capmatinib is a small molecule kinase inhibitor targeted against c-Met (a.k.a. hepatocyte growth factor receptor ), a receptor tyrosine kinase that, in healthy humans, activates signaling cascades involved in organ regeneration and tissue repair. Aberrant c-Met activation - via mutations, amplification, and/or overexpression - is known to occur in many types of cancer, and leads to overactivation of multiple downstream signaling pathways such as STAT3, PI3K/ATK, and RAS/MAPK. Mutations in _MET_ have been detected in non-small cell lung cancer (NSCLC), and the prevalence of _MET_ amplification in epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI)-naive patients with NSCLC has been reported to be 1.4% - 21%. This co-occurrence has made c-Met a desirable target in the treatment of NSCLC. Manufactured by Novartis and marketed under the brand name Tabrecta, capmatinib was granted accelerated approval by the FDA on May 6, 2020, for the treatment of NSCLC in patients whose tumors have a mutation that leads to mesenchymal-epithelial transition (MET) exon 14 skipping. The presence of the mutation must be confirmed by an FDA-approved test, such as the FoundationOne CDx assay (manufactured by Foundation Medicine, Inc.), which was approved by the FDA on the same day. As this indication was granted under an accelerated approval, its continued approval is contingent upon verification of capmatinib's benefit in confirmatory trials. Capmatinib was approved by Health Canada on June 8, 2022.

Indications:

This drug is primarily indicated for: In the US, capmatinib is indicated for the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have a mutation that leads to mesenchymal-epithelial transition (MET) exon 14 skipping as detected by an FDA-approved test. Capmatinib is approved to treat adults with locally advanced unresectable or metastatic non-small cell lung cancer (NSCLC) with MET exon 14 skipping alterations in Canada. Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Capmatinib undergoes metabolic processing primarily in: Capmatinib undergoes metabolism primarily via CYP3A4 and aldehyde oxidase. Specific biotransformation pathways and metabolic products have yet to be elucidated. This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Capmatinib are crucial for its therapeutic efficacy: The oral bioavailability of capmatinib is estimated to be >70%. Following oral administration, maximum plasma concentrations are achieved within 1 to 2 hours (T_max). Co-administration with a high-fat meal increased capmatinib AUC by 46% with no change in C_max (as compared to fasted conditions), and co-administration with a low-fat meal had no clinically meaningful effects on exposure. The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Capmatinib is an important consideration for its dosing schedule: The elimination half-life is 6.5 hours. This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Capmatinib exhibits a strong affinity for binding with plasma proteins: Plasma protein binding is approximately 96% and is independent of drug serum concentration. This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Capmatinib from the body primarily occurs through: Following oral administration of radiolabeled capmatinib, approximately 78% of the radioactivity is recovered in feces, of which ~42% is unchanged parent drug, and 22% is recovered in the urine, of which a negligible amount remains unchanged parent drug. Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Capmatinib is distributed throughout the body with a volume of distribution of: The apparent volume of distribution at steady-state is 164 L. This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Capmatinib is a critical factor in determining its safe and effective dosage: The mean apparent clearance of capmatinib at steady-state is 24 L/h. It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Capmatinib exerts its therapeutic effects through: Capmatinib inhibits the overactivity of c-Met, a receptor tyrosine kinase encoded by the _MET_ proto-oncogene. Mutations in _MET_ are involved in the proliferation of many cancers, including non-small cell lung cancer (NSCLC). Capmatinib may cause photosensitivity reactions in patients following ultraviolet (UV) exposure - patients undergoing therapy with capmatinib should be advised to use sunscreen and protective clothing to limit exposure to UV radiation. Instances of interstitial lung disease/pneumonitis, which can be fatal, occurred in patients being treated with capmatinib. Patients presenting with signs or symptoms of lung disease (e.g. cough, dyspnea, fever) should have capmatinib immediately withheld, and capmatinib should be permanently discontinued if no other feasible causes of the lung-related symptoms are identified. The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Capmatinib functions by: Aberrant activation of c-Met has been documented in many cancers, including non-small cell lung cancer (NSCLC). Mutations that result in the skipping of _MET_ exon 14 lead to the formation of a mutant c-Met with a missing regulatory domain - these mutant proteins have a reduced ability to negatively regulate, leading to a pathological increase in their downstream activity. Capmatinib inhibits the phosphorylation of both wild-type and mutant variants of c-Met triggered by the binding of its endogenous ligand, hepatocyte growth factor - in doing so, it prevents c-Met-mediated phosphorylation of downstream signaling proteins, as well as the proliferation and survival of c-Met-dependent tumor cells. This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Classification:

Capmatinib belongs to the class of organic compounds known as quinolines and derivatives. These are compounds containing a quinoline moiety, which consists of a benzene ring fused to a pyrimidine ring to form benzo[b]azabenzene, classified under the direct parent group Quinolines and derivatives. This compound is a part of the Organic compounds, falling under the Organoheterocyclic compounds superclass, and categorized within the Quinolines and derivatives class, specifically within the None subclass.

Categories:

Capmatinib is categorized under the following therapeutic classes: Acids, Carbocyclic, Amides, Antineoplastic Agents, Antineoplastic and Immunomodulating Agents, BCRP/ABCG2 Inhibitors, Benzene Derivatives, Benzoates, Cytochrome P-450 CYP1A2 Inhibitors, Cytochrome P-450 CYP1A2 Inhibitors (strength unknown), Cytochrome P-450 CYP3A Substrates, Cytochrome P-450 CYP3A4 Substrates, Cytochrome P-450 Enzyme Inhibitors, Cytochrome P-450 Substrates, Kinase Inhibitor, MATE 1 Inhibitors, MATE 2 Inhibitors, MATE 2-K Inhibitors, MATE inhibitors, Mesenchymal Epithelial Transition Inhibitors, P-glycoprotein inhibitors, P-glycoprotein substrates, Protein Kinase Inhibitors, Tyrosine Kinase Inhibitors. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.