Capmatinib

Breast Feeding; Lactation; Milk, Human; Enzyme Inhibitors; Protein Kinase Inhibitors; Signal Transduction Inhibitors

EMA approved medicines: Human medicine

Danger

H301 (100%): Toxic if swallowed [Danger Acute toxicity, oral]

P203, P260, P264, P270, P273, P280, P301+P316, P318, P319, P321, P330, P391, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 8 reports by companies from 2 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

In the prelicensure clinical trials of capmatinib in patients with solid tumors harboring MET mutations, liver test abnormalities were frequent although usually self-limited and mild. Some degree of ALT elevations arose in 39% of capmatinib treated patients and were above 5 times the upper limit of normal (ULN) in 7%. In these trials that enrolled 373 patients, capmatinib was discontinued early due to increased AST or ALT in only 1% of patients. The liver test abnormalities had a median onset of 2 months after initiation of therapy. While serum aminotransferase elevations were occasionally quite high (5 to 20 times upper limit of normal), there were no accompanying elevations in serum bilirubin and no patient developed clinically apparent liver injury with jaundice. The product label for capmatinib recommends monitoring for routine liver tests before, at 2-week intervals during the first 3 months of therapy, and monthly thereafter as clinically indicated. However, since its approval and more wide-spread clinical use, there have been several reports of acute liver injury with jaundice in patients receiving capmatinib. The onset is after 6 to 8 weeks, and the clinical pattern is hepatocellular with features resembling severe acute viral hepatitis. Immune allergic and autoimmune features are not common, and recovery occurs typically within 2 to 3 months, but at least one fatal incident has been reported. Strikingly, most cases have occurred shortly after previous chemotherapy with a checkpoint inhibitor (within 2 to 4 months of the last dose). A similar frequent occurrence of liver injury following recent use of checkpoint inhibitors has been reported with other kinase inhibitors (sotorasib, crizotinib, osimertinib). These findings suggest that capmatinib not be started within 4 months of the last dose of a checkpoint inhibitor.

L - Antineoplastic and immunomodulating agents

QL - Antineoplastic and immunomodulating agents

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.

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.

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CAPMATINIB

Established Pharmacologic Class [EPC] - Kinase Inhibitor

Mechanisms of Action [MoA] - Mesenchymal Epithelial Transition Inhibitors

Mechanisms of Action [MoA] - Cytochrome P450 1A2 Inhibitors

Mechanisms of Action [MoA] - P-Glycoprotein Inhibitors

The oral bioavailability of capmatinib is estimated to be >70%. Following oral administration, maximum plasma concentrations are achieved within 1 to 2 hours (Tmax). Co-administration with a high-fat meal increased capmatinib AUC by 46% with no change in Cmax (as compared to fasted conditions), and co-administration with a low-fat meal had no clinically meaningful effects on exposure.

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.

The apparent volume of distribution at steady-state is 164 L.

The mean apparent clearance of capmatinib at steady-state is 24 L/h.