Wang Rongrong, Li Yanfen, Zhang Ran, Ren Yuan, Liu Yifan, Wang Tianlin, Wu Jin, Zheng Xiangjin, Li Shu, Jing Yu
Department of Pharmacy, Medical Supplies Center, Chinese PLA General Hospital, Beijing, China.
Department of Hematology in the Fifth Medical Center of PLA General Hospital, Beijing, China.
Front Pharmacol. 2025 May 30;16:1539233. doi: 10.3389/fphar.2025.1539233. eCollection 2025.
Azole antifungals inhibit the enzyme cytochrome P450 3A4 (CYP 3A4), increasing venetoclax (VEN) levels and the risk of serious adverse reactions. Dose adjustments for VEN with voriconazole (VOR) vary in studies. The drug-drug interactions (DDI), safety and economic implications of VEN with VOR in the Chinese population, who may have unique drug exposures, are unclear. This study aims to address these uncertainties and provide guidance for clinical practice.
The DDI were assessed by measuring trough (Ctrough) and peak (Cpeak) levels of VEN and concomitant azoles after ≥7 days of continuous administration. Safety and economic implications were evaluated based on the duration of cytopenias and hospitalization costs for Chinese patients with acute myeloid leukemia (AML) across three groups: VEN 400 mg, VEN 100 mg combined with posaconazole (POS) (VEN 100 mg + POS) and VEN 100 mg combined with VOR (VEN 100 mg + VOR).
VOR was able to significantly increase the Ctrough (3.40 vs. 0.99, ) μg/mL and Cpeak (3.71 vs. 2.22, ) μg/mL of VEN 100 mg compared to VEN 400 mg alone. This increase in the plasma concentration of VEN may result in a longer duration of days to white blood cell (WBC) > 2000 cells/mm (25 vs. 13, ) and a higher likelihood of increased hospitalization costs (140,469 vs. 73,513, ) compared to VEN 400 mg alone.
Chinese population may require further dose reduction of VEN beyond guideline recommendations when combined with VOR.
唑类抗真菌药可抑制细胞色素P450 3A4（CYP 3A4）酶，提高维奈克拉（VEN）水平并增加严重不良反应风险。在研究中，VEN与伏立康唑（VOR）联用的剂量调整有所不同。VEN与VOR在中国人群中的药物相互作用（DDI）、安全性和经济影响尚不清楚，而中国人群可能有独特的药物暴露情况。本研究旨在解决这些不确定性问题，并为临床实践提供指导。
在连续给药≥7天后，通过测量VEN及联用唑类药物的谷浓度（Ctrough）和峰浓度（Cpeak）来评估DDI。基于三组中国急性髓系白血病（AML）患者的血细胞减少持续时间和住院费用，评估安全性和经济影响，这三组分别为：VEN 400 mg、VEN 100 mg联合泊沙康唑（POS）（VEN 100 mg + POS）以及VEN 100 mg联合VOR（VEN 100 mg + VOR）。
与单独使用VEN 400 mg相比，VOR能够显著提高VEN 100 mg的Ctrough（分别为3.40与0.99，）μg/mL和Cpeak（分别为3.71与2.22，）μg/mL。与单独使用VEN 400 mg相比，VEN血浆浓度的这种升高可能导致白细胞（WBC）> 2000个细胞/mm的天数更长（分别为25与13，），且住院费用增加的可能性更高（分别为140,469与73,513，）。
在中国人群中，VEN与VOR联用时可能需要在指南推荐基础上进一步降低剂量。
