Drug Interactions between doravirine and Kisqali Femara Co-Pack

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as well as clinical and laboratory monitoring may be appropriate for some drugs whenever ribociclib is added to or withdrawn from therapy.

Coadministration with inhibitors of CYP450 3A4 may increase the plasma concentrations of doravirine, which is primarily metabolized by the isoenzyme. In 10 study subjects, administration of a single 50 mg dose of doravirine with the potent CYP450 3A4 inhibitor ritonavir (100 mg twice daily) increased doravirine peak plasma concentration (Cmax), systemic exposure (AUC) and trough plasma concentration (C24hr) by an average of 31%, 254% and 191%, respectively, compared to administration of doravirine alone. When a single 100 mg dose of doravirine was administered with ketoconazole 400 mg once daily in 10 study subjects, doravirine Cmax, AUC and C24hr increased by an average of 25%, 206% and 175%, respectively. These changes are not considered clinically significant.