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药物不良反应已成为一个公共卫生问题,其中约30%为药物相互作用(drug-drug interactions,DDIs)所导致[1]。DDI指的是2种以上的药物同时或先后使用时,其中一种药物受到另一种药物的影响而发生理化性质、药动学和药效学明显改变。有文献报道,药动学相互作用发生率最高,约占DDIs的40%[2]。已有研究表明,环孢素A(cyclosporineA,CsA)和伏立康唑(voriconazole,VRZ)之间存在着一定的DDI。VRZ体内呈非线性药动学,主要通过肝脏CYP2C19代谢,其次通过CYP2C9和CYP3A4代谢,CYP2C19呈现基因多态性,个体间的药物代谢和相互作用存在很大差异[3]。同时,CYP3A4是CsA的主要代谢酶,而VRZ对CYP3A4代谢酶具有抑制作用。因此,当CsA和VRZ两药联用时,CsA的代谢会受到抑制,血药浓度升高、体内药物蓄积,导致肝肾毒性等不良反应事件的发生。对于临床医生,如何充分认识和管理好DDI具有较大的挑战性。本研究将在Allo-HSCT患者中,通过自身前后对照研究,探讨VRZ血药浓度与CsA血药浓度的升高幅度是否有相关性,CsA与VRZ相互作用是否存在个体性差异,以指导临床对CsA和VRZ的合理使用。本研究已通过联勤保障部队第九四〇医院伦理委员会审批(2019KYLL039),并签署患者知情同意书。
Interaction between cyclosporine A and voriconazole in patients with allogeneic hematopoietic stem cell transplantation
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摘要:
目的 分析异基因造血干细胞移植(Allo-HSCT)患者,静脉滴注伏立康唑(VRZ)与环孢素A(CsA)后的药物相互作用(DDI),为临床精准药物治疗提供依据。 方法 进行一项患者自身对照研究,根据纳入排除标准,收集2019年1月—12月在某院进行Allo-HSCT的患者,采用LC-MS/MS法测定术前CsA给药后3~5 d的血药浓度2次,测定术后VRZ给药5~7 d后,CsA和VRZ同一时间的血药浓度2次,分别求其给药前后CsA、VRZ血药浓度的平均值。使用SPSS 20.0对VRZ给药前后CsA标准化血药浓度(C/D)的差异及VRZ血药浓度对CsA的C/D变化进行统计分析。 结果 共纳入Allo-HSCT患者15例,用Wilcoxon符号秩和检验比较给药VRZ前后,CsA的C/D中位数变化,有显著性差异(P<0.001)。对VRZ血药浓度与CsA的C/D比值增幅进行Spearman相关性分析,两者无显著相关性(ρ=−0.273,P=0.32)。 结论 CsA与VRZ之间存在明显的药物相互作用(DDI),VRZ使CsA血药浓度显著升高,但VRZ与CsA之间的DDI程度大小与VRZ血药浓度无关,可能与患者个体差异有关。 Abstract:Objective To analyze the drug-drug interaction (DDI) between intravenous voriconazole (VRZ) and intravenous cyclosporine (CsA) in patients after allogeneic hematopoietic stem cell transplantation (Allo-HSCT) and provide an individualized and accurate clinical drug delivery. Methods In a self-contrast study, Allo-HSCT patients from January 2019 to December 2019 were enrolled according to the inclusion and exclusion criteria. These patients were treated with CsA and VRZ successively and the blood concentration of CsA and VRZ before and after 5-7 days of VRZ administration were determined with LC-MS/MS. The correlation between the concentration of VRZ and concentration/dose (C/D) ratio of CsA was analyzed with SPSS20.0. Results A total of 15 patients with ALLo-HSCT were enrolled. Wilcoxon sign rank sum test was used to compare the change of median C/D of CsA before and after VRZ administration, which had shown significant difference (P<0.001). Spearman correlation analysis was conducted on the increase of C/D ratio between VRZ and CsA, which had no significant correlation between them (ρ=−0.273, P=0.32). Conclusions There was obvious drug-drug interaction (DDI) between CsA and VRZ. VRZ increased CsA blood concentration significantly, but there was no significant correlation between VRZ blood concentration and the degree of concentration increase, which might be related to individual difference. -
Key words:
- CsA /
- VRZ /
- blood concentration /
- therapeutic drug monitoring /
- drug interaction
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