Drug interactions of Capmatinib

Capmatinib is primarily metabolized by CYP3A4 and aldehyde oxidase. In vitro studies have demonstrated that capmatinib reversibly inhibits multidrug and toxin extrusion (MATE) 1 and 2K, but does not inhibit organic anion-transporting polypeptide (OATP) 1B1 or 1B3, organic cation transporter (OCT) 1, organic anion transporter (OAT) 1 or 3, or multidrug resistance-associated protein 2 (MRP2). In vitro studies have also indicated that capmatinib is a substrate of P-glycoprotein (P-gp); it is not a substrate of breast cancer resistance protein (BCRP) or MRP2.

Drugs Affecting Hepatic Microsomal Enzymes

Strong CYP3A inhibitors: May increase the systemic exposure and risk of adverse reactions to capmatinib. Monitor closely for adverse reactions.

Moderate or strong CYP3A inducers: May decrease the plasma concentration of capmatinib and reduce its efficacy. Avoid concomitant use.

Drugs Metabolized by Hepatic Microsomal Enzymes

CYP1A2 substrates: May increase the plasma concentration and risk of adverse reactions to CYP1A2 substrates. Avoid concomitant use of capmatinib with CYP1A2 substrates that have a narrow therapeutic window. If concomitant use is unavoidable, reduce the dosage of the substrate drug.

CYP3A substrates: No clinically significant effect on the pharmacokinetics of sensitive CYP3A substrates.

Substrates of Drug Transport Systems

P-gp substrates: May increase the plasma concentration and risk of adverse reactions to P-gp substrates. Avoid concomitant use of capmatinib with P-gp substrates that have a narrow therapeutic window. If concomitant use is unavoidable, reduce the dosage of the substrate drug.

BCRP substrates: May increase the plasma concentration and risk of adverse reactions to BCRP substrates. Avoid concomitant use of capmatinib with BCRP substrates that have a narrow therapeutic window. If concomitant use is unavoidable, reduce the dosage of the substrate drug.

MATE1 or MATE2K substrates: May increase the plasma concentration and risk of adverse reactions to MATE1 or MATE2K substrates. Avoid concomitant use of capmatinib with MATE1 or MATE2K substrates that have a narrow therapeutic window. If concomitant use is unavoidable, reduce the dosage of the substrate drug.

Specific Drugs

Caffeine: Capmatinib increased the AUC of caffeine (a CYP1A2 substrate) by 134%.

Digoxin: Capmatinib increased the AUC and peak concentration of digoxin (a P-gp substrate) by 47% and 74%, respectively. Recommendation: Avoid concomitant use; if unavoidable, reduce the dosage of digoxin.

Efavirenz: Efavirenz (a moderate CYP3A inducer) is predicted to decrease the AUC and peak concentration of capmatinib by 44% and 34%, respectively. Recommendation: Avoid concomitant use.

Itraconazole: Itraconazole (a strong CYP3A inhibitor) increased the AUC of capmatinib by 42%. Recommendation: Monitor closely for capmatinib-related adverse reactions.

Midazolam: No substantial effect on the exposure of midazolam (a CYP3A substrate).

Rabeprazole: Rabeprazole (a gastric acid inhibitor) decreased the AUC and peak concentration of capmatinib by 25% and 38%, respectively.

Rifampicin: Rifampicin (a strong CYP3A inducer) decreased the AUC and peak concentration of capmatinib by 67% and 56%, respectively. Recommendation: Avoid concomitant use.

Rosuvastatin: Capmatinib increased the AUC and peak concentration of rosuvastatin (a BCRP substrate) by 108% and 204%, respectively. Recommendation: Avoid concomitant use; if unavoidable, reduce the dosage of rosuvastatin.

from FDA,2023.03