Abstract：
Nirmatrelvir/ritonavir association has been authorized for conditional use in the treatment of COVID-19, especially in solid-organ transplant recipients who did not respond to vaccine and are still at high risk of severe disease. This combination remains at risk of drug interactions with immunosuppressants, so monitoring drug levels seems necessary. After a simple protein precipitation of plasma sample, analytes were analyzed using an ultrahigh performance liquid chromatography system coupled with tandem mass spectrometry in a positive ionization mode. Validation procedures were based on the guidelines on bioanalytical methods issued by the European Medicine Agency. The analysis time was 4 min per run. The calibration curves were linear over the range from 10 to 1000 ng/mL for ritonavir and 40 to 4000 ng/mL for nirmatrelvir, with coefficients of correlation above 0.99 for all analytes. Intra-/interday imprecisions were below 10%. The analytical method also meets criteria of matrix effect, carryover, dilution integrity, and stability. In the context of a SARS-CoV-2 infection in a renal transplant recipient, we present a case of tacrolimus overdose with serious adverse events despite discontinuation of nirmatrelvir and ritonavir. The patient had still effective concentrations of nirmatrelvir and tacrolimus 4 days after drug discontinuation. This method was successfully applied for therapeutic drug monitoring in clinical practice.
摘要：
Nirmatrelvir/ritonavir协会已被授权有条件地用于治疗COVID-19，特别是在对疫苗无反应且仍有严重疾病高风险的实体器官移植受者中。这种组合仍然存在与免疫抑制剂药物相互作用的风险，所以监测药物水平似乎是必要的。在血浆样品的简单蛋白质沉淀后，分析物使用超高效液相色谱系统与串联质谱联用以正离子模式进行分析。验证程序基于欧洲药品管理局发布的生物分析方法指南。分析时间为每次运行4分钟。利托那韦的校准曲线在10至1000ng/mL的范围内是线性的，尼马特雷韦的校准曲线在40至4000ng/mL的范围内是线性的，所有分析物的相关系数都在0.99以上。日内/日间不精确度低于10%。分析方法也符合基体效应的标准，结转,稀释完整性，和稳定性。在肾移植受者的SARS-CoV-2感染的背景下，我们介绍了1例他克莫司用药过量,尽管停用尼马特雷韦和利托那韦,但出现严重不良事件.停药后4天，患者仍有有效浓度的尼马特雷韦和他克莫司。该方法已成功应用于临床治疗药物监测。
