cate that ribociclib is extensively metabolized, primarily via CYP3A4. After a single, radio-labeled, 600 mg dose, the primary metabolic pathway for ribociclib involved combinations of oxidation (dealkylation, C and/or N-oxygenation, oxidation (-2H)). In a drug interaction trial, coadministration with ritonavir, a strong CYP3A4 inhibitor, increased the Cmax and AUC of ribociclib by 1.7-fold and 3.2-fold, respectively, in healthy volunteers; the Cmax and AUC of M4, a prominent metabolite accounting for less than 10% of parent exposure, decreased by 96% and 98%, respectively. Coadministration with a moderate CYP3A4 inhibitor is predicted to increase the Cmax and AUC of ribociclib by 1.3-fold and 1.9-fold, respectively. In another drug interaction trial, coadministration with a rifampicin, a strong CYP3A4 inducer, decreased the Cmax and AUC of ribociclib by 81% and 89%, respectively; the Cmax of M4 increased by 1.7-fold and the AUC decreased by 27%. A moderate CYP3A4 inducer is predicted to decrease the Cmax and AUC of ribociclib by 37% and 60%, respectively.
Ribociclib is a reversible and time-dependent inhibitor of CYP3A4/5 at clinically relevant concentrations in vitro, as well as a reversible inhibitor of CYP1A2 and CYP2E1 in vitro. In a drug interaction trial in healthy subjects, coadministration of ribociclib 400 mg once daily increased the Cmax and AUC of midazolam, a sensitive CYP3A4 substrate, by 2.3-fold and 3.8-fold, respectively; administration of the recommended dose of ribociclib (600 mg daily) is predicted to increase the Cmax and AUC of midazolam by 2.4-fold and 5.2-fold, respectively. Multiple daily doses of ribociclib 400 mg decreased the Cmax and AUC of caffeine, a CYP1A2 substrate, by 10% and 20%, respectively; only weak inhibitory effects on CYP1A2 substrates are predicted at the recommended dosing.
Additionally, ribociclib may inhibit BCRP, OCT2, MATE1, and human BSEP at clinically relevant concentrations. Ribociclib has a low potential to inhibit P-glycoprotein (P-gp), OATP1B1/B3, OCT1, and MATEK2. In human microsomes with specific CYP isozyme activity, CYP3A4 metabolized letrozole to the carbinol metabolite while CYP2A6 formed both this metabolite and its ketone analog. In human liver microsomes, letrozole inhibited CYP2A6 and inhibited CYP2C19, however, the clinical significance of these findings is unknown.
Oral Route
After both single and repeated doses, ribociclib exhibited over-proportional increases in Cmax and AUC across a dose range of 50 mg to 1,200 mg. The Tmax after oral administration of ribociclib was between 1 and 4 hours. The rate and extent of ribociclib absorption were not affected by administration with a high-fat, high-calorie meal compared to administration in a fasting state, with the geometric mean Cmax of 1 (90% CI, 0.898 to 1.11) and geometric mean AUC of 1.06 (90% CI, 1.01 to 1.12). Letrozole is rapidly and completely absorbed from the gastrointestinal tract; absorption is not affected by food.
In postmenopausal patients with advanced breast cancer, daily doses of letrozole (range, 0.1 mg to 5 mg) suppressed plasma concentrations of estradiol, estrone, and estrone sulfate by 75% to 95% from baseline; maximal suppression was achieved within 2 to 3 days. Suppression is dose-related, with doses of 0.5 mg and higher giving many values of estrone and estrone sulfate that were below the limit of detection in the assays. Estrogen suppression was maintained throughout treatment in all patients treated at 0.5 mg or higher.& |
