Effect of Cytochrome P450 3A Inhibition and Induction by Itraconazole and Rifampin on Tazemetostat Pharmacokinetics in Patients With Advanced Malignancies

This study (NCT04537715) investigated itraconazole (strong cytochrome P450 [CYP] 3A inhibitor) and rifampin (strong CYP3A inducer) on tazemetostat pharmacokinetics. In Part 1, patients received tazemetostat 400 mg orally on Days 1, 15, and 36, and 400 mg twice daily on Days 3-14 and Days 21-35. Itraconazole 200 mg orally once daily was administered on Days 18-38. In Part 2, patients received tazemetostat 800 mg orally once daily on Days 1, 15, and 24, and 800 mg twice daily on Days 3-14 and Days 17-23. Rifampin 600 mg orally once daily was administered on Days 17-25. Twenty-one patients in each part completed had plasma concentrations quantified for pharmacokinetic assessments. Itraconazole coadministration resulted in higher tazemetostat exposures after single doses (Day 21/Day 1) and steady state (Day 36/Day 15). Compared with tazemetostat alone, itraconazole increased mean maximum plasma concentration (C_max) and area under the concentration-time curve from time 0 to 12 hours (AUC_0-12h) by 2.00- and 3.12-fold, respectively, after single doses. Following twice-daily dosing, itraconazole increased mean steady-state C_max and AUC_0-12h by 1.86- and 2.47-fold, respectively. Rifampin coadministration decreased tazemetostat steady-state (C_max) and AUC_0-12h by approximately 84% (Day 24/Day 15). Itraconazole increased tazemetostat exposure by 2-3-fold, and rifampin decreased tazemetostat exposure by 84%, indicating that coadministration of tazemetostat with strong CYP3A inhibitors or inducers should be avoided.