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

Year: 2025

Type: article

Abstract: 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 (Cmax) and area under the concentration‐time curve from time 0 to 12 hours (AUC0‐12h) by 2.00‐ and 3.12‐fold, respectively, after single doses. Following twice‐daily dosing, itraconazole increased mean steady‐state Cmax and AUC0‐12h by 1.86‐ and 2.47‐fold, respectively. Rifampin coadministration decreased tazemetostat steady‐state (Cmax) and AUC0‐12h 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.

Source: Clinical Pharmacology in Drug Development

DOI: 10.1002/cpdd.1543