Cusato Jessica, Palermiti Alice, Manca Alessandra, Mula Jacopo, Antonucci Miriam, De Nicolò Amedeo, Allegra Sarah, De Francia Silvia, Chiara Francesco, Di Perri Giovanni, Rosa Francesco Giuseppe De, Calcagno Andrea, D'Avolio Antonio
Laboratory of Clinical Pharmacology and Pharmacogenetics, Department of Medical Sciences, University of Turin, Amedeo di Savoia Hospital, 10149 Turin, Italy.
ASL Città di Torino, Amedeo di Savoia Hospital, 10149 Turin, Italy.
Pharmaceuticals (Basel). 2022 May 20;15(5):630. doi: 10.3390/ph15050630.
Vitamin D (VD) seems to influence drug clearance and outcome. Antifungal drugs (AFU) are the most used azoles in clinical practice. In the literature, no data are available concerning VD's impact on AFU therapy. The aim of this study was to analyze if VD pathway-related polymorphisms may influence voriconazole (VRC), itraconazole (ITC), and posaconazole (PSC) drug concentrations in order to identify patients with the highest probability of response and toxicity. Allelic discrimination was performed through real-time PCR, whereas drug concentrations were through liquid chromatography. A total of 636 samples of AFU-treated patients were included in the analysis. Concerning VRC, concentrations higher than the 1000 ng/mL efficacy cut-off value were predicted by Caucasian ethnicity, 3999, and + 2838 polymorphisms, whereas levels higher than the 5000 ng/mL toxicity value by Caucasian, female sex, e.v. administration, and 1296. Considering PSC, concentrations higher than the 700 ng/mL efficacy cut-off value were predicted by Cdx2, - 1260, and 1296. Finally, for ITC, BsmI was the only predictor of drug exposure higher than the 500 ng/mL efficacy cut-off value, whereas female sex, - 1260, and TaqI remained in the final regression model related to concentrations higher than the 1000 ng/mL toxicity-associated cut-off value. This is the first study reporting the influence of VD pathway-related gene SNPs on AFU exposures, efficacy, and toxicity.
维生素D（VD）似乎会影响药物清除率和治疗结果。抗真菌药物（AFU）是临床实践中最常用的唑类药物。在文献中，尚无关于VD对AFU治疗影响的数据。本研究的目的是分析VD途径相关的基因多态性是否会影响伏立康唑（VRC）、伊曲康唑（ITC）和泊沙康唑（PSC）的药物浓度，以确定反应和毒性可能性最高的患者。通过实时PCR进行等位基因鉴别，而药物浓度则通过液相色谱法测定。分析共纳入了636例接受AFU治疗的患者样本。关于VRC，白种人、3999和 + 2838基因多态性可预测浓度高于1000 ng/mL的疗效临界值，而白种人、女性、静脉给药和1296可预测浓度高于5000 ng/mL的毒性值。对于PSC，Cdx2、 - 1260和1296可预测浓度高于700 ng/mL的疗效临界值。最后，对于ITC，BsmI是药物暴露高于500 ng/mL疗效临界值的唯一预测因素，而女性、 - 1260和TaqI仍在与浓度高于1000 ng/mL毒性相关临界值的最终回归模型中。这是第一项报道VD途径相关基因单核苷酸多态性对AFU暴露、疗效和毒性影响的研究。
