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High-throughput Identification of Synergistic Drug Combinations by the Overlap2 Method
Published on: May 21, 2018
Pharmacokinetic interaction between SHR2554 and fluconazole: A single-center, open-label and one-sequence crossover
Yuyang Dai1, Minwan Hu2, Shaojie Guo1
1National Institute for Drug Clinical Trial, Beijing Tongren Hospital, Capital Medical University, No. 1 Dongjiaominxiang Road, Beijing 100730, PR China.
Abstract:
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.
Insights
The investigational drug SHR2554, an EZH2 inhibitor, showed significantly increased drug levels when taken with fluconazole, a CYP3A4 inhibitor. Caution is advised during co-administration due to potential drug-drug interactions.
Area of Science:
- Pharmacology
- Oncology
- Drug Metabolism
Background:
- SHR2554 is a selective oral EZH2 inhibitor with potential in hematologic malignancies.
- CYP3A4 metabolism of SHR2554 poses a risk for drug-drug interactions (DDIs).
Purpose of the Study:
- To assess the pharmacokinetic impact of fluconazole, a moderate CYP3A4 inhibitor, on SHR2554.
- To evaluate the safety profile of SHR2554 when co-administered with fluconazole.
Main Methods:
- A single-center, open-label, single-dose, crossover Phase I trial involving 18 healthy Chinese subjects.
- Subjects received SHR2554 alone and in combination with fluconazole.
- Pharmacokinetic parameters (Cmax, AUC0-t, AUC0-∞) and adverse events were monitored.
Main Results:
- Co-administration with fluconazole significantly increased SHR2554 exposure: Cmax by 3.29-fold, AUC0-t by 4.79-fold, and AUC0-∞ by 4.13-fold.
- Treatment-emergent adverse events were generally mild and transient.
- No serious adverse events were reported during the study.
Conclusions:
- Fluconazole significantly increases SHR2554 systemic exposure, indicating a potential for DDIs.
- Clinical use of SHR2554 with moderate CYP3A4 inhibitors requires careful consideration and dose adjustment.
- Findings are crucial for optimizing future clinical trial designs and patient management.
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