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

Year: 2025

Type: article

Abstract: 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.

Source: Clinical and Translational Science

DOI: 10.1111/cts.70330