Dataset Information

Effect of itraconazole and fluconazole on the pharmacokinetics of valemetostat: An open-label, phase I study in healthy subjects.

ABSTRACT: Valemetostat tosylate (valemetostat) is an oral, potent, dual inhibitor of enhancer of zeste homolog (EZH) 2 and EZH1 under investigation for the treatment of cancer, including non-Hodgkin's lymphomas and solid tumors. Itraconazole and fluconazole are antifungal medications often used as typical inhibitors of cytochrome P450 3A (CYP3A [itraconazole and fluconazole]) and P-glycoprotein (P-gp [itraconazole]) in drug-drug interaction studies. Valemetostat is a substrate of CYP3A and P-gp in vitro. This phase I, open-label, single-sequence crossover study (JapicCTI-183902) assessed the pharmacokinetics (PK) of valemetostat when co-administered with itraconazole (a strong CYP3A inhibitor and P-gp inhibitor) or fluconazole (a moderate CYP3A inhibitor) in healthy Japanese male participants 20-45 years of age. Participants were equally allocated to receive two doses of valemetostat 25 mg, once alone and once with either itraconazole or fluconazole (400-mg induction and 200-mg once daily maintenance). Valemetostat PK parameters with versus without itraconazole or fluconazole were compared using analysis of variance models. Overall, 32 participants were enrolled. Co-administration with itraconazole increased valemetostat peak concentration (C_max ) by 2.9-fold and area under the plasma concentration-time curve extrapolated to infinity (AUC_inf ) by 4.2-fold compared with valemetostat alone. When co-administered with fluconazole, the C_max and AUC_inf of valemetostat were each increased by 1.6-fold. No treatment-related or grade ≥3 adverse events were reported. Appropriate valemetostat dose reductions are warranted when used concomitantly with strong CYP3A and P-gp dual inhibitors.

SUBMITTER: Tachibana M

PROVIDER: S-EPMC10651645 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature

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Effect of itraconazole and fluconazole on the pharmacokinetics of valemetostat: An open-label, phase I study in healthy subjects.

Tachibana Masaya M Matsuki Shunji S Maekawa Yutaro Y Kuroda Kana K Shimizu Takako T Tsutsumi Junko J Ishizuka Hitoshi H

Clinical and translational science 20230913 11

Valemetostat tosylate (valemetostat) is an oral, potent, dual inhibitor of enhancer of zeste homolog (EZH) 2 and EZH1 under investigation for the treatment of cancer, including non-Hodgkin's lymphomas and solid tumors. Itraconazole and fluconazole are antifungal medications often used as typical inhibitors of cytochrome P450 3A (CYP3A [itraconazole and fluconazole]) and P-glycoprotein (P-gp [itraconazole]) in drug-drug interaction studies. Valemetostat is a substrate of CYP3A and P-gp in vitro. ...[more]

PMID: 37705321

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Dataset Information

Effect of itraconazole and fluconazole on the pharmacokinetics of valemetostat: An open-label, phase I study in healthy subjects.

Publications

Effect of itraconazole and fluconazole on the pharmacokinetics of valemetostat: An open-label, phase I study in healthy subjects.

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