Therapeutic Drug Monitoring of Tacrolimus-Personalized Therapy: Second Consensus Report
Therapeutic Drug Monitoring of Tacrolimus-Personalized Therapy: Second Consensus Report
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DOI：
10.1097/ftd.0000000000000640
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发表时间：
2019-06-01
影响因子：
2.5
通讯作者：
Bergan, Stein
中科院分区：
文献类型：
--
作者：
Brunet, Merce;van Gelder, Teun;Bergan, Stein
十年前，本刊发表了一篇关于他克莫司优化的共识报告。2017年，国际治疗药物监测和临床毒性协会(IATDMCT)免疫抑制药物科学委员会决定发布一份最新的共识报告，考虑他克莫司药代动力学(PK)、药物遗传学(PG)、药效学和免疫生物标志物方面最相关的进展，旨在提供分析和药物暴露建议，以帮助TDM专业人员和临床医生个性化他克莫司TDM和治疗。这一共识是基于对本文件中涉及的每个主题的深入文献搜索。他克莫司及其PG和生物标记物TDM领域的37名国际专家为起草与他们的专长最相关的章节作出了贡献。只要适用，证据的质量和建议的力度都根据出版的评级指南进行评级。经过反复编辑后，所有作者都批准了完整文件的最终版本。对于每一类实体器官和干细胞移植，讨论了PK监测的现状，并提出了亚组患者的他克莫司谷浓度(剂量前样本C-0)的具体目标以及这些建议的分级。此外，他克莫司浓度-时间曲线下面积的测定被认为是移植后早期、免疫抑制最小化时、特殊人群和特殊临床情况下的最佳TDM选择。对于移植以外的适应症，系统治疗中潜在有效的他克莫司浓度在没有正式分级的情况下讨论。强调了一致性、校准、能力测试的重要性，以及标准化的要求和对可追溯性和参考材料的需要。介绍了他克莫司TDM的替代方法的现状，包括干血斑、容量吸收微量采样和细胞内他克莫司测量的发展。CYP3A5基因与他克莫司剂量需求的相关性是一致的(A-I级)。到目前为止，药效学和免疫学生物标志物还没有进入常规监测，但检测活化T细胞调节基因表达的残存核因子有助于识别有排斥、感染和恶性肿瘤风险的肾移植受者(B II)。此外，监测细胞内T细胞干扰素-g的产生有助于确定肾和肝移植受者有急性排斥反应的高风险(B II)，并选择免疫抑制最小化(B II)的良好候选者。尽管无细胞DNA似乎是一个有前景的急性供体损伤的生物标志物，并评估他克莫司的最低有效C-0，但需要进行多中心前瞻性干预研究，以更好地评估其在实体器官移植中的临床应用价值。包括CYP3A5和CYP3A4基因在内的群体PK模型将被考虑用于指导他克莫司的初始给药。未来的研究应该调查事件发生时间模型的临床益处，以更好地评估预测个人反应、排斥反应风险和移植结果的生物标记物。专家委员会的结论是，在过去的十年中，他克莫司监测的不同领域已经取得了相当大的进展。继续努力的重点应该是有机会在临床常规中实施新的标准化PK方法与PG和有效的生物标志物的结合，以进一步个性化他克莫司治疗并改善接受治疗的患者的长期结果。
Ten years ago, a consensus report on the optimization of tacrolimus was published in this journal. In 2017, the Immunosuppressive Drugs Scientific Committee of the International Association of Therapeutic Drug Monitoring and Clinical Toxicity (IATDMCT) decided to issue an updated consensus report considering the most relevant advances in tacrolimus pharmacokinetics (PK), pharmacogenetics (PG), pharmacodynamics, and immunologic biomarkers, with the aim to provide analytical and drug-exposure recommendations to assist TDM professionals and clinicians to individualize tacrolimus TDM and treatment. The consensus is based on in-depth literature searches regarding each topic that is addressed in this document. Thirty-seven international experts in the field of TDM of tacrolimus as well as its PG and biomarkers contributed to the drafting of sections most relevant for their expertise. Whenever applicable, the quality of evidence and the strength of recommendations were graded according to a published grading guide. After iterated editing, the final version of the complete document was approved by all authors. For each category of solid organ and stem cell transplantation, the current state of PK monitoring is discussed and the specific targets of tacrolimus trough concentrations (predose sample C-0) are presented for subgroups of patients along with the grading of these recommendations. In addition, tacrolimus area under the concentration-time curve determination is proposed as the best TDM option early after transplantation, at the time of immunosuppression minimization, for special populations, and specific clinical situations. For indications other than transplantation, the potentially effective tacrolimus concentrations in systemic treatment are discussed without formal grading. The importance of consistency, calibration, proficiency testing, and the requirement for standardization and need for traceability and reference materials is highlighted. The status for alternative approaches for tacrolimus TDM is presented including dried blood spots, volumetric absorptive microsampling, and the development of intracellular measurements of tacrolimus. The association between CYP3A5 genotype and tacrolimus dose requirement is consistent (Grading A I). So far, pharmacodynamic and immunologic biomarkers have not entered routine monitoring, but determination of residual nuclear factor of activated T cells-regulated gene expression supports the identification of renal transplant recipients at risk of rejection, infections, and malignancy (B II). In addition, monitoring intracellular T-cell IFN-g production can help to identify kidney and liver transplant recipients at high risk of acute rejection (B II) and select good candidates for immunosuppression minimization (B II). Although cell-free DNA seems a promising biomarker of acute donor injury and to assess the minimally effective C-0 of tacrolimus, multicenter prospective interventional studies are required to better evaluate its clinical utility in solid organ transplantation. Population PK models including CYP3A5 and CYP3A4 genotypes will be considered to guide initial tacrolimus dosing. Future studies should investigate the clinical benefit of time-to-event models to better evaluate biomarkers as predictive of personal response, the risk of rejection, and graft outcome. The Expert Committee concludes that considerable advances in the different fields of tacrolimus monitoring have been achieved during this last decade.Continued efforts should focus on the opportunities to implement in clinical routine the combination of new standardized PK approaches with PG, and valid biomarkers to further personalize tacrolimus therapy and to improve long-term outcomes for treated patients.