Abstract CT029: The effect of tazemetostat on CYP3A-mediated metabolism of midazolam in patients with solid tumors

Abstract

Abstract Background: Tazemetostat is a selective oral small molecule inhibitor of enhancer of zeste homolog 2 (EZH2). Results from in vitro studies using human liver microsomes, recombinant CYP isoforms, and hepatocytes demonstrated that tazemetostat is an inhibitor, inducer, and substrate of CYP3A4. Previous results indicated that systemic exposure to tazemetostat decreased after multiple dose administration in patients with cancer, consistent with net induction of CYP3A-mediated metabolism. Therefore, a drug-drug interaction sub-study was performed as part of the ongoing study E7438-G000-101 (NCT01897571). Purpose: To investigate the effect of tazemetostat on CYP3A-mediated metabolism in patients with solid tumors using midazolam as a sensitive CYP3A probe substrate. Methods: This was a single-sequence, open-label, crossover study. Patients with solid tumors (n = 13) received a single oral dose of 2 mg midazolam on Day -1 and on Day 15. Tazemetostat 800 mg twice daily (BID) was administered continuously starting on Day 1. Serial blood samples for the analysis of plasma midazolam and metabolites were collected over 24 h on Day -1 (midazolam alone) and Day 15 (midazolam plus tazemetostat). Results: A summary of midazolam pharmacokinetic parameters after administration alone and with tazemetostat 800 mg BID in 12 evaluable patients is presented below: ParameterDay -1aDay 15aGLSMRb (90% CI)AUC(0-∞) ng*h/mL51.9 (87.2)31.1 (48.1)0.60 (0.46, 0.78)Cmax ng/mL16.5 (94.3)13.0 (48.3)0.78 (0.57, 1.08)t1/2 h5.67 (34.3)4.25 (32.4)NCaData presented as geometric mean (%CV)bGLSMR = geometric least squares mean ratioNC = not calculated Plasma midazolam AUC(0-?) and Cmax decreased approximately 40% and 22%, respectively, after administration with tazemetostat 800 mg BID relative to administration of midazolam alone. Geometric mean t1/2 for midazolam decreased approximately 25%, after administration of midazolam with tazemetostat 800 mg BID relative to administration of midazolam alone. Conclusions: Administration of tazemetostat 800 mg BID resulted in net induction of CYP3A-mediated metabolism in patients with cancer. Tazemetostat 800 mg BID resulted in a less than 50% decrease in midazolam AUC and therefore is a weak inducer of CYP3A-mediated metabolism. Citation Format: Sherri Smith, Benjamin Suttle, Nigel L. Waters, Vincent Ribrag, Antoine Italiano, Jean-Marie Michot, Sophie Postel-Vinay, Maud Toulmonde, Sophie Cousin, Maria Roche, Patricia Pimentel, Peter Ho. The effect of tazemetostat on CYP3A-mediated metabolism of midazolam in patients with solid tumors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT029.