Supplementary Material for: Predictive Value of FMO3 Variants on Plasma Disposition and Adverse Reactions of Oral Voriconazole in Febrile Neutropenia

Background and Objectives: With the increasing number of patients with febrile neutropenia (FN), voriconazole (VRC) has been widely used in hospitals for first-line treatment of FN. The study was designed for evaluating the influence of FMO3 mutation on the plasma disposition and adverse reactions of VRC in FN. Materials and Methods: A single-center observational study was conducted in the inpatient ward for 4 years. The genotypes of FMO3 and cytochrome P450 (CYP) 2C19 were detected by PCR-restriction fragment length polymorphism. Patients with neutropenia were screened according to the CYP2C19 metabolic phenotype and other inclusion criteria. Five days after empirical administration of VRC, blood concentrations of VRC and nitrogen oxides in patients’ blood were determined by liquid chromatography-electrospray tandem mass spectrometry (LC-ESI MS/MS). Serum parameters and clinical adverse reaction symptoms in the medical records were collected and statistically analyzed. Results: A total of 165 patients with neutropenia with the intermediate metabolic phenotype of CYP2C19 were screened. At the initial stage of oral VRC treatment, patients with the FMO3 E308G genotype had a poorer plasma disposal ability to VRC than those with the wide type of FMO3 (WT) genotype (p = 0.0005). Moreover, patients with the FMO3 E308G genotype were more likely to have adverse drug reactions and abnormal serum parameters after receiving VRC treatment. For example, the serum potassium level in the FMO3 E308G genotype group was significantly lower than that in the WT group (p = 0.028), the abnormal level of total bilirubin in the FMO3 E308G genotype group was significantly higher than that in the WT group (p = 0.049), and the aspartate aminotransferase level in the E308G group was significantly higher than that in the WT group (p = 0.05). The incidence of atopic dermatitis and visual impairment in the FMO3 E308G genotype group was 67 and 75%, respectively, and the incidences of peripheral neuroedema, headache, and diarrhea were 57, 50, and 60%, respectively, which were significantly different from those in the WT group. Conclusion: FMO3 E308G reduces the activity of the FMO3 enzyme by decreasing the metabolic ability of VRC, which increases the plasma concentration of VRC and may also lead to adverse reactions in patients with FN.研究背景与目的：随着发热性中性粒细胞减少症（febrile neutropenia, FN）患者数量日益增多，伏立康唑（voriconazole, VRC）已在临床医院中被广泛用于发热性中性粒细胞减少症的一线治疗。本研究旨在评估FMO3基因突变对伏立康唑在发热性中性粒细胞减少症患者体内的血浆处置过程及不良反应的影响。 研究对象与方法：本研究为单中心观察性研究，在住院病房开展，为期4年。采用聚合酶链式反应-限制性片段长度多态性（PCR-restriction fragment length polymorphism）技术检测受试者的FMO3与细胞色素P450（cytochrome P450, CYP）2C19基因型。根据CYP2C19代谢表型及其他纳入标准筛选中性粒细胞减少症患者。在经验性给予伏立康唑治疗5天后，采用液相色谱-电喷雾串联质谱法（liquid chromatography-electrospray tandem mass spectrometry, LC-ESI MS/MS）检测患者血液中的伏立康唑血药浓度与氮氧化物含量。收集病历中的血清学指标及临床不良反应症状，并进行统计学分析。 研究结果：本研究共筛选出165例CYP2C19中等代谢表型的中性粒细胞减少症患者。在口服伏立康唑治疗初期，携带FMO3 E308G基因型的患者对伏立康唑的血浆清除能力弱于野生型（wild type, WT）FMO3基因型患者（p=0.0005）。此外，携带FMO3 E308G基因型的患者在接受伏立康唑治疗后，更易出现药物不良反应及血清学指标异常。例如，FMO3 E308G基因型组患者的血清钾水平显著低于野生型组（p=0.028），总胆红素异常水平显著高于野生型组（p=0.049），天冬氨酸氨基转移酶水平亦显著高于野生型组（p=0.05）。FMO3 E308G基因型组患者的特应性皮炎、视力障碍发生率分别为67%、75%，外周神经水肿、头痛及腹泻发生率分别为57%、50%、60%，上述指标与野生型组相比均存在显著差异。 研究结论：FMO3 E308G基因突变可通过降低伏立康唑的代谢能力、削弱FMO3酶活性，进而升高伏立康唑的血浆浓度，可能会增加发热性中性粒细胞减少症患者出现不良反应的风险。