Drug Interaction Report

MONITOR: Coadministration with inhibitors of P-glycoprotein (P-gp) may increase the plasma concentrations of daunorubicin and idarubicin, both of which are substrates of the efflux transporter also known as ABCB1 or MDR1. The interaction has been studied with cyclosporine, a potent P-gp inhibitor, in attempt to overcome multidrug resistance in MDR1-overexpressing tumors. In a randomized study to test whether cyclosporine can enhance the antileukemia effect of anthracyclines, cyclosporine was found to significantly reduce the frequency of resistance to induction chemotherapy consisting of sequential cytarabine and daunorubicin (31% vs. 47%). The addition of cyclosporine also increased relapse-free and overall survival, particularly in patients with moderate or high P-gp expression. Pharmacokinetically, steady-state mean serum concentrations of daunorubicin and its active metabolite, daunorubicinol, were significantly higher (approximately 2-fold and 4-fold, respectively) in patients receiving cyclosporine. Although there was no significant difference in the frequency or severity of stomatitis or renal toxicity (as measured by creatinine elevation), grade 4 hyperbilirubinemia and grade 3 nausea occurred more frequently in patients receiving cyclosporine than in controls (31% vs. 4% and 11% vs. 3%, respectively). In a pharmacokinetic study of 27 patients with acute myelogenous leukemia receiving induction chemotherapy with idarubicin and cytarabine, the systemic exposure (AUC) to idarubicin and idarubicinol was increased by 77% and 182%, respectively, in patients administered cyclosporine 10 mg/kg daily compared to controls due to a 40% reduction in total body clearance. The interaction was also reported in another study in which increases in the AUC of idarubicin and idarubicinol were associated with increased levels of toxicity.

MANAGEMENT: Caution is advised if daunorubicin or idarubicin is prescribed in combination with a P-gp inhibitor. Patients should be closely monitored for increased adverse effects including cardiotoxicity and myelosuppression.

ADJUST DOSING INTERVAL: Food may reduce the oral bioavailability of asciminib. When a single 40 mg dose of asciminib was administered with a low-fat meal (400 calories; 25% fat) in healthy volunteers, asciminib peak plasma concentration (Cmax) and systemic exposure (AUC) decreased by 35% and 30%, respectively, compared to asciminib administered in the fasted state. Administration with a high-fat meal (1000 calories; 50% fat) decreased the Cmax and AUC of asciminib by 68% and 62%, respectively.

MANAGEMENT: To ensure adequate asciminib exposures, food consumption should be avoided for at least 2 hours before and 1 hour after taking asciminib.