Department of Pharmacy, National Cerebral and Cardiovascular Center, Suita, Japan.
Division of Clinical Drug Informatics, School of Pharmacy, Kindai University, Higashi-osaka, Japan.
Eur J Clin Pharmacol. 2020 Jan;76(1):117-125. doi: 10.1007/s00228-019-02770-6. Epub 2019 Oct 26.
This study investigated the effects of clotrimazole troche on the risk of transplant rejection and the pharmacokinetics of tacrolimus.
The data mining approach was used to investigate whether the use of clotrimazole increased the risk of transplant rejection in patients receiving tacrolimus therapy. Patient data were acquired from the US Food and Drug Administration's Adverse Event Reporting System (FAERS) from the first quarter of 2004 to the end of 2017. Next, we retrospectively investigated the effect of clotrimazole troche on tacrolimus pharmacokinetics in seven patients who underwent heart transplantation between March and December 2017.
The FAERS subset data indicated a significant association between transplant rejection and tacrolimus with clotrimazole [reporting odds ratio 1.92, 95% two-sided confidence interval (95% CI) 1.43-2.58, information component 0.81, 95% CI 0.40-1.23]. The pharmacokinetic study demonstrated a significant correlation between trough concentration (C) and area under the concentration-time curve of tacrolimus after discontinuation of clotrimazole (R = 0.60, P < 0.05) but not before its discontinuation. Furthermore, the median clearance/bioavailability of tacrolimus after discontinuation of clotrimazole was 2.2-fold greater than that before its discontinuation (0.27 vs. 0.59 L/h/kg, P < 0.05). The median C decreased from 10.7 ng/mL on the day after discontinuation of clotrimazole to 6.5 ng/mL at 1 day and 5.3 ng/mL at 2 days after its discontinuation.
Immediate dose adjustments of tacrolimus may be beneficial to avoid transplant rejection when clotrimazole troche is added or discontinued.
本研究旨在探讨克霉唑含漱剂对移植排斥反应风险和他克莫司药代动力学的影响。
采用数据挖掘方法，研究克霉唑的使用是否会增加接受他克莫司治疗的患者发生移植排斥反应的风险。患者数据来自美国食品和药物管理局不良事件报告系统（FAERS），时间范围为 2004 年第一季度至 2017 年底。随后，我们回顾性调查了克霉唑含漱剂在 2017 年 3 月至 12 月期间接受心脏移植的 7 例患者中对他克莫司药代动力学的影响。
FAERS 子数据集表明，移植排斥反应与克霉唑和他克莫司之间存在显著关联[报告比值比 1.92，95%双侧置信区间（95%CI）1.43-2.58，信息成分 0.81，95%CI 0.40-1.23]。药代动力学研究表明，克霉唑停药后，他克莫司的谷浓度（C）和浓度-时间曲线下面积（AUC）之间存在显著相关性（R = 0.60，P <0.05），但在停药前无此相关性。此外，克霉唑停药后他克莫司的清除率/生物利用度中位数是停药前的 2.2 倍（0.27 比 0.59 L/h/kg，P <0.05）。克霉唑停药后第 1 天 C 从 10.7 ng/mL 降至 6.5 ng/mL，第 2 天降至 5.3 ng/mL。
当克霉唑含漱剂添加或停用后，立即调整他克莫司的剂量可能有助于避免移植排斥反应。
