Drug Interactions between larotrectinib and letrozole / ribociclib

MONITOR: Coadministration with ribociclib may increase the plasma concentrations and pharmacologic effects of drugs that are substrates of CYP450 3A4. The proposed mechanism is decreased clearance due to ribociclib-mediated inhibition of CYP450 3A4 metabolism. In healthy study subjects, administration of midazolam, a sensitive CYP450 3A4 substrate, with multiple 400 mg daily doses of ribociclib increased the midazolam peak plasma concentration (Cmax) and systemic exposure (AUC) by 2.1-fold and 3.8-fold, respectively, compared to midazolam administered alone. When given at a clinically relevant dose of 600 mg daily, ribociclib is predicted to increase midazolam Cmax and AUC by 2.4-fold and 5.2-fold, respectively.

MANAGEMENT: Caution is advised when ribociclib is used concomitantly with drugs that undergo metabolism by CYP450 3A4, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever ribociclib is added to or withdrawn from therapy.

MONITOR: Coadministration with larotrectinib may increase the plasma concentrations of drugs that are substrates of the CYP450 3A4 isoenzyme. In study subjects, coadministration of midazolam, a sensitive CYP450 3A4 substrate, with larotrectinib 100 mg twice daily increased midazolam peak plasma concentration (Cmax) and systemic exposure (AUC) by 1.7-fold each compared to administration of midazolam alone. The Cmax and AUC of 1-hydroxymidazolam, the main metabolite of midazolam, were both increased by 1.4-fold.

MANAGEMENT: Caution is advised when larotrectinib is used concomitantly with drugs that are substrates of CYP450 3A4, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever larotrectinib is added to or withdrawn from therapy. Patients should be monitored for the development of adverse effects. Some authorities recommend avoiding concomitant use of larotrectinib and sensitive CYP450 3A4 substrates or substrates with narrow therapeutic ranges. These drugs include, but are not limited to: alfentanil, cisapride, colchicine, cyclosporine, fentanyl, ivacaftor, lovastatin, simvastatin, oral midazolam, triazolam, pimozide, quinidine, sildenafil, ergot derivatives, macrolide immunosuppressants, and vinca alkaloids.

MONITOR: Coadministration with inhibitors of CYP450 3A4, P-glycoprotein (P-gp), and/or breast cancer resistance protein (BCRP) may increase the plasma concentrations of larotrectinib. According to the prescribing information, larotrectinib is metabolized primarily by the CYP450 3A4 isoenzyme and is a substrate of the P-gp and BCRP efflux transporters in vitro. When a single 100 mg dose of larotrectinib was coadministered with itraconazole (200 mg once daily for 7 days), a potent CYP450 3A4 inhibitor and P-gp/BCRP inhibitor, larotrectinib peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 2.8- and 4.3-fold, respectively, compared to administration of larotrectinib alone. When a single 100 mg dose of larotrectinib was administered in healthy adult subjects with a single 600 mg dose of rifampin (a P-gp and BCRP inhibitor during initial use, but an inducer of CYP450 3A4 and P-gp following chronic use), larotrectinib Cmax and AUC increased by 1.8- and 1.7-fold, respectively. Coadministration with fluconazole, a moderate CYP450 3A4 inhibitor, is predicted to increase larotrectinib steady-state Cmax by 1.9-fold and AUC by 2.7-fold.

MANAGEMENT: Caution is advised when larotrectinib is used with CYP450 3A4, P-gp, and/or BCRP inhibitors. Patients should be monitored more frequently for adverse effects such as neurotoxicity (delirium, dysarthria, dizziness, gait disturbance, paraesthesia, encephalopathy, memory impairment, tremor) and hepatotoxicity (elevations in liver transaminases), and the larotrectinib dosage adjusted based on severity of emergent adverse reactions in accordance with the product labeling.