Pharmacokinetic interaction between SHR2554 and fluconazole: A single-center, open-label and one-sequence crossover phase I trial in healthy Chinese subjects

SHR2554, a highly selective oral EZH2 inhibitor, shows promise in treating hematologic malignancies. However, its metabolism via CYP3A4 raises concerns about drug-drug interactions. This study evaluates the impact of fluconazole, a moderate CYP3A4 inhibitor, on the pharmacokinetics and safety implic...

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Veröffentlicht in:European journal of pharmaceutical sciences Jg. 212; S. 107163
Hauptverfasser: Dai, Yuyang, Hu, Minwan, Guo, Shaojie, Wu, Feng, Han, Ying, Ni, Siyang, Li, Shaorong, Zhu, Zhenyu, Yuan, Weilan, Zhao, Xiuli
Format: Journal Article
Sprache:Englisch
Veröffentlicht: Netherlands Elsevier B.V 01.09.2025
Schlagworte:
Adult
Antifungal Agents - administration & dosage
Antifungal Agents - pharmacokinetics
Area Under Curve
Cross-Over Studies
CYP3A4
Cytochrome P-450 CYP3A - metabolism
Cytochrome P-450 CYP3A Inhibitors - administration & dosage
Cytochrome P-450 CYP3A Inhibitors - pharmacokinetics
Drug Interactions
Drug-drug interaction
East Asian People
EZH2 inhibitor
Female
Fluconazole
Fluconazole - administration & dosage
Fluconazole - adverse effects
Fluconazole - pharmacokinetics
Fluconazole - pharmacology
Healthy Volunteers
Humans
Male
SHR2554
Young Adult
SHR2554
Fluconazole
Drug-drug interaction
CYP3A4
EZH2 inhibitor
ISSN:0928-0987, 1879-0720, 1879-0720
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Zusammenfassung:SHR2554, a highly selective oral EZH2 inhibitor, shows promise in treating hematologic malignancies. However, its metabolism via CYP3A4 raises concerns about drug-drug interactions. This study evaluates the impact of fluconazole, a moderate CYP3A4 inhibitor, on the pharmacokinetics and safety implications of SHR2554. We conducted a single-center, open-label, single-dose, single-sequence crossover phase I trial. 18 Chinese healthy subjects were orally administered SHR2554 100 mg on Day 1, fluconazole 400 mg on Day 4 and 200 mg QD from Days 5 to 6. SHR2554 100 mg co-administrated with fluconazole 200 mg on Day 7, and fluconazole 200 mg QD from Days 8 to 9. Pharmacokinetic parameters were compared after subjects were administered SHR2554 alone and in combination with fluconazole. Cmax, AUC0-t, and AUC0-∞ were significantly increased when SHR2554 was co-administered with fluconazole. The co-administration led to a 3.29-, 4.79-, and 4.13-fold increase in Cmax, AUC0-t, and AUC0-∞, respectively. Safety evaluations indicated that the observed treatment-emergent adverse events were mild and transient. These findings underline the necessity of caution when co-administered SHR2554 with moderate CYP3A4 inhibitors in clinical settings, providing crucial insights for optimizing future clinical trials. [Display omitted]
Bibliographie:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:0928-0987
1879-0720
1879-0720
DOI:10.1016/j.ejps.2025.107163