Document Type
Article
Publication Date
10-28-2025
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 (Cmax) (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 (AUClast) (GMR, 0.87 [90% CI, 0.75–1.03]), increased digoxin Cmax (GMR, 1.30 [90% CI, 1.07–1.57]), and AUClast (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.
Recommended Citation
Tachibana, Masaya; Horwitz, Steven; Jacobsen, Eric; Foss, Francine; Allen, Pamela; Porcu, Pierluigi; Feldman, Tatyana; Ruan, Jia; Brammer, Jonathan; Wang, Jie; Inaba, Shinichi; Iko, Yuka; Nakajima, Keiko; Kakurai, Yasuyuki; Kitami, Noriaki; Chen, Yang; and Lau, Yvonne, "Effect of Valemetostat on the Pharmacokinetics of Midazolam and Digoxin: A Phase 1 Drug-Drug Interaction Study in Patients With Non-Hodgkin Lymphoma" (2025). Department of Medicine Faculty Papers. Paper 523.
https://jdc.jefferson.edu/medfp/523
Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.
PubMed ID
41150706
Language
English
Included in
Chemical and Pharmacologic Phenomena Commons, Hematology Commons, Hemic and Lymphatic Diseases Commons, Internal Medicine Commons, Neoplasms Commons
Comments
This article is the author’s final published version in Clinical and Translational Science, Volume 18, Issue 11, 2025, Article number e70330.
The published version is available at https://doi.org/10.1111/cts.70330. Copyright © 2025 The Author(s).