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

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 typica...

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Vydáno v:	Clinical and translational science Ročník 16; číslo 11; s. 2153 - 2162
Hlavní autoři:	Tachibana, Masaya, Matsuki, Shunji, Maekawa, Yutaro, Kuroda, Kana, Shimizu, Takako, Tsutsumi, Junko, Ishizuka, Hitoshi
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States John Wiley & Sons, Inc 01.11.2023 Wiley
Témata:	Antifungal agents Area Under Curve Beverages Cross-Over Studies Cytochrome Cytochrome P-450 CYP3A - metabolism Cytochrome P-450 CYP3A Inhibitors Cytochrome P450 Drug dosages Drug interaction Drug Interactions Enzyme Inhibitors Fluconazole Fluconazole - adverse effects Glycoproteins Healthy Volunteers Humans Itraconazole Itraconazole - adverse effects Leukemia Lymphoma Male Neoplasms Non-Hodgkin's lymphoma P-Glycoprotein Pharmaceuticals Pharmacokinetics Plasma Solid tumors Japan
ISSN:	1752-8054, 1752-8062, 1752-8062
On-line přístup:	Získat plný text
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Shrnutí:	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.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 ObjectType-Undefined-3
ISSN:	1752-8054 1752-8062 1752-8062
DOI:	10.1111/cts.13613