Effect of Valemetostat on the Pharmacokinetics of Midazolam and Digoxin: A Phase 1 Drug-Drug Interaction Study in Patients With Non-Hodgkin Lymphoma.

Overview

abstract

Valemetostat tosylate (valemetostat) is an oral, potent, dual inhibitor of enhancer of zeste homolog (EZH)2/1, under investigation in non-Hodgkin lymphomas (NHLs) and solid tumors. In vitro, it inhibits cytochrome P450 3A (CYP3A) and P-glycoprotein (P-gp) when combined with sensitive CYP3A or P-gp substrates. This drug-drug interaction (DDI) sub-study is part of the phase 1 trial of valemetostat monotherapy (DS3201-A-J101; NCT02732275), assessing the effect of valemetostat on the pharmacokinetics (PK) of sensitive CYP3A and P-gp substrates midazolam and digoxin, respectively, in patients with relapsed or refractory NHL, and its safety and efficacy. Patients received two simultaneous single doses of midazolam and digoxin: once alone and once concomitantly with a daily 200 mg valemetostat dose in a 28-day cycle. Of 24 enrolled patients, 15 and 16 were evaluable for PK analyses of midazolam and digoxin, respectively. Valemetostat co-administration caused a slight decrease in midazolam maximum plasma concentration (C_max) (geometric least-squares mean ratio [GMR], 0.966 [90% confidence interval (CI), 0.769-1.21]) and area under the plasma concentration-time curve up to the last quantifiable time (AUC_last) (GMR, 0.87 [90% CI, 0.75-1.03]), increased digoxin C_max (GMR, 1.30 [90% CI, 1.07-1.57]), and AUC_last (GMR, 1.27 [90% CI, 1.06-1.52]). The overall safety and efficacy outcomes were similar to other studies. Valemetostat showed a manageable and tolerable safety profile, without clinically meaningful DDI with sensitive CYP3A substrates. Co-administration of valemetostat and P-gp substrates with a narrow therapeutic index may require careful monitoring and/or DDI risk management.