Drug Interactions between letrozole / ribociclib and seladelpar

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as well as clinical and laboratory monitoring may be appropriate for some drugs whenever ribociclib is added to or withdrawn from therapy.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: Concomitant use with a moderate to potent CYP450 3A4 inhibitor may significantly increase seladelpar's exposure in patients who are CYP450 2C9 poor metabolizers. The proposed mechanism is reduced clearance of seladelpar, which is primarily metabolized via CYP450 2C9 and to a lesser extent via CYP450 3A4 and 2C8. The activity of CYP450 2C9 is decreased in individuals with genetic variants of the isoenzyme. After a single dose of seladelpar (1 mg to 15 mg), dose-normalized systemic exposure (AUC) was 48% higher in CYP450 2C9 poor metabolizers (n=2) and 24% higher in CYP450 2C9 intermediate metabolizers (n=28) compared to normal metabolizers (n=84). However, the maximum plasma concentration (Cmax) was similar regardless of metabolizer status. These increases in AUC are not considered clinically relevant alone. Similarly, physiologically based pharmacokinetic model simulations predicted that coadministration with the potent CYP450 3A4 inhibitor itraconazole (300 mg daily) and the moderate CYP450 3A4 inhibitor erythromycin (500 mg 4 times daily) increased seladelpar's AUC by 34% and 24% and its Cmax by 18% and 14%, respectively. These changes were also not considered clinically relevant alone. However, use of a concomitant moderate to potent CYP450 3A4 inhibitor in a patient classified as a CYP450 2C9 poor metabolizer may result in clinically significant changes. While in vivo data specific to this scenario are lacking, coadministration with the moderate CYP450 2C9 and 3A4 inhibitor fluconazole (400 mg) increased the AUC of seladelpar (10 mg) by 2.4-fold, which was considered clinically significant.

MANAGEMENT: If concomitant use of a moderate to potent CYP450 3A4 inhibitor is clinically necessary during treatment with seladelpar, caution and determining the patient's CYP450 2C9 genotype may be advisable. Patients who are classified as poor CYP450 2C9 metabolizers should be monitored more closely for adverse reactions (e.g., abnormal liver function tests) during coadministration. Should adverse reactions occur, treatment with seladelpar may need to be held or permanently discontinued as indicated by the manufacturer. The labeling of the inhibitor should also be consulted as some inhibitors may continue to have effects on CYP450 3A4 even after the agent has been discontinued.