Abstract

1. Voriconazole (VRC) is a first-line drug for the treatment of invasive fungal infections (IFIs) and an inhibitor of CYP3A activity. The aims of this study are to investigate the influence of related factors on the plasma concentration of voriconazole and the effect of voriconazole on the activity of CYP3A in patients with haematological malignancies.

2. A total of 89 patients received an initial dose of 6 mg/kg followed by 4 mg/kg every 12 h were included in the study. Blood samples were collected before and 2 h after administration for subsequent testing and for the extraction of DNA samples. Voriconazole and voriconazole N-oxide in the plasma were detected by LC-MS/MS. The effect of voriconazole on CYP3A activity was evaluated by the ratio of the endogenous biomarkers 6β-hydroxycortisol and cortisol.

3. During the study period, the overall incidence of adverse reactions was 33.6% (with no deaths). The metabolite type of CYP2C19 and combined use of CYP2C19 enzyme inhibitors both had a significant impact on voriconazole exposure. Voriconazole has a long-lasting and potent inhibitory effect on CYP3A activity. The exposure of CYP3A substrate in combination with metabolic enzyme inhibitors voriconazole could increase. Therefore, the combination uses with voriconazole need to be considered carefully and assessed adequately.

摘要

1. 伏立康唑 (VRC) 是治疗侵袭性真菌感染 (IFI) 的一线药物，也是 CYP3A 活性的抑制剂。本研究旨在探讨相关因素对血液系统恶性肿瘤患者伏立康唑血药浓度的影响以及伏立康唑对CYP3A活性的影响。

2. 共有 89 名患者接受了 6 mg/kg 的初始剂量，随后每 12 小时 4 mg/kg 剂量被纳入研究。在给药前和给药后 2 小时采集血样用于后续检测和 DNA 样本的提取。通过LC-MS/MS检测血浆中的伏立康唑和伏立康唑N-氧化物。通过内源性生物标志物 6β-羟基皮质醇和皮质醇的比率评估伏立康唑对 CYP3A 活性的影响。

3. 在研究期间，不良反应的总发生率为33.6%（无死亡）。CYP2C19的代谢物类型和CYP2C19酶抑制剂的联合使用都对伏立康唑的暴露有显着影响。伏立康唑对 CYP3A 活性具有持久而有效的抑制作用。CYP3A 底物与代谢酶抑制剂伏立康唑联合的暴露可能会增加。因此，需要仔细考虑与伏立康唑的组合使用并进行充分评估。