Personalization of pharmacotherapy with sirolimus based on volumetric absorptive microsampling (VAMS) in pediatric renal transplant recipients-from LC-MS/MS method validation to clinical application.

IF 3.6 3区医学 Q2 PHARMACOLOGY & PHARMACY

Pharmacological Reports Pub Date : 2024-10-10 DOI:10.1007/s43440-024-00663-9

Arkadiusz Kocur, Agnieszka Czajkowska, Kamila Rębis, Jacek Rubik, Mateusz Moczulski, Bartłomiej Kot, Maciej Sierakowski, Tomasz Pawiński

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引用次数: 0

Abstract

Background: The benefits of pharmacotherapy with sirolimus (SIR) in pediatric transplant recipients are well established. Traditionally, whole blood samples have been used to measure SIR concentrations. Volumetric Absorptive Microsampling (VAMS) is an alternative sampling strategy suitable for Therapeutic Drug Monitoring (TDM). In this study, we developed and validated two liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods for determining SIR concentrations in whole blood (WB) and capillary whole blood samples collected using a VAMS-Mitra™ device.

Methods: We used protein precipitation during WB sample preparation and dispersive liquid-liquid microextraction (DLLME) with methyl tert-butyl ether for VAMS sample preparation to optimise the analyte extraction process. The described validation protocols were cross-validated, confirming the equivalence of the whole-blood and VAMS-based methods. Furthermore, the developed methods were evaluated in two three-level rounds of an external proficiency-testing scheme.

Results: The analytical methods were successfully validated within the calibration range of SIR (0.5-60 ng/ml). The validation parameters met the European Medicines Agency (EMA) and the International Association of Therapeutic Drug Monitoring and Clinical Toxicology (IATDM&CT) acceptance criteria. No hematocrit (tested in the range of 24.3-64.1%), matrix, or carry-over effects were observed. Cross-validation confirmed the interchangeability between VAMS-LC-MS/MS and WB-LC-MS/MS methods. The developed methods were successfully implemented for SIR determination in 140 clinical samples (70 each of WB and VAMS) from pediatric renal transplant recipients, demonstrating their practicality and reliability.

Conclusion: The VAMS-based method has been rigorously tested and is clinically equivalent to the reference WB-LC-MS/MS method. Additionally, clinical validation confirmed the utility of the presented methods for TDM of the SIR in the pediatric population after renal transplantation.

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基于体积吸收微采样（VAMS）的小儿肾移植受者西罗莫司个性化药物治疗--从 LC-MS/MS 方法验证到临床应用。

背景：西罗莫司（SIR）药物疗法对儿科移植受者的益处已得到公认。传统上使用全血样本来测量西罗莫司的浓度。体积吸收微量采样（VAMS）是一种适用于治疗药物监测（TDM）的替代采样策略。在这项研究中，我们开发并验证了两种液相色谱-串联质谱（LC-MS/MS）方法，用于测定使用 VAMS-Mitra™ 设备采集的全血（WB）和毛细管全血样本中的 SIR 浓度：我们在制备 WB 样品时使用了蛋白质沉淀法，在制备 VAMS 样品时使用了甲基叔丁基醚分散液-液微萃取 (DLLME)，以优化分析物的萃取过程。对所描述的验证方案进行了交叉验证，确认了基于全血和 VAMS 方法的等效性。此外，还在外部能力测试计划的两轮三级测试中对所开发的方法进行了评估：结果：分析方法在 SIR 的校准范围（0.5-60 纳克/毫升）内得到了成功验证。验证参数符合欧洲药品管理局（EMA）和国际治疗药物监测和临床毒理学协会（IATDM&CT）的验收标准。未观察到血细胞比容（测试范围为 24.3-64.1%）、基质或携带效应。交叉验证证实了 VAMS-LC-MS/MS 和 WB-LC-MS/MS 方法之间的互换性。所开发的方法已成功应用于小儿肾移植受者的 140 份临床样本（WB 和 VAMS 各 70 份）的 SIR 测定，证明了这些方法的实用性和可靠性：结论：基于 VAMS 的方法已经过严格测试，在临床上等同于参考 WB-LC-MS/MS 方法。此外，临床验证证实了所介绍的方法在肾移植后儿科人群中用于 SIR 的 TDM 的实用性。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Pharmacological Reports 医学-药学

CiteScore

8.40

自引率

0.00%

发文量

审稿时长

6 months

期刊介绍： Pharmacological Reports publishes articles concerning all aspects of pharmacology, dealing with the action of drugs at a cellular and molecular level, and papers on the relationship between molecular structure and biological activity as well as reports on compounds with well-defined chemical structures. Pharmacological Reports is an open forum to disseminate recent developments in: pharmacology, behavioural brain research, evidence-based complementary biochemical pharmacology, medicinal chemistry and biochemistry, drug discovery, neuro-psychopharmacology and biological psychiatry, neuroscience and neuropharmacology, cellular and molecular neuroscience, molecular biology, cell biology, toxicology. Studies of plant extracts are not suitable for Pharmacological Reports.