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选择合适的他克莫司剂量。

Choosing the right dose of tacrolimus.

作者信息

Lancia Pauline, Jacqz-Aigrain Evelyne, Zhao Wei

机构信息

Department of Pediatric Pharmacology and Pharmacogenetics, Hôpital Robert Debré, APHP, Paris, France EA7323, Université Paris Diderot-Université Paris Descartes, Paris, France.

Department of Pediatric Pharmacology and Pharmacogenetics, Hôpital Robert Debré, APHP, Paris, France EA7323, Université Paris Diderot-Université Paris Descartes, Paris, France Clinical Investigation Center CIC1426, INSERM, Paris, France.

出版信息

Arch Dis Child. 2015 Apr;100(4):406-13. doi: 10.1136/archdischild-2013-305888. Epub 2014 Nov 21.

Abstract

Choosing the right dose of tacrolimus 'adapted to each individual patient' is a central question after transplantation. The pharmacokinetic behaviour of tacrolimus in paediatric patients is significantly influenced by clinical factors growth and maturation, as well as genetic factors. Large interindividual variability and narrow therapeutic index make dosage individualisation mandatory in children. CYP3A5 expressers require a 1.8-fold higher tacrolimus dose than non-expressers. A visual patient-tailored dosing chart, taking into consideration the child's weight, recent haematocrit level and CYP3A5 genotype, was developed based on a population pharmacokinetic-pharmacogenetic model, and can be used routinely to individualise tacrolimus starting dose. Area under the concentration-time curve-based dosage adaptation through limited sampling strategy and Bayesian estimation is more reliable than trough concentration. Therapeutic drug monitoring and dosage adaptation can be included in routine post-transplantation consultation and should be considered in the urgent situations (eg, rejection, adverse event, lack of compliance, change of coadministration drug with potential drug-drug interaction and other situations).

摘要

选择“适合每个患者个体”的他克莫司正确剂量是移植后的核心问题。他克莫司在儿科患者中的药代动力学行为受到临床因素(生长和成熟)以及遗传因素的显著影响。个体间差异大且治疗指数窄使得儿童必须进行剂量个体化。CYP3A5表达者所需的他克莫司剂量比非表达者高1.8倍。基于群体药代动力学-药物遗传学模型开发了一个可视的患者定制给药图表,该图表考虑了儿童体重、近期血细胞比容水平和CYP3A5基因型,可常规用于他克莫司起始剂量的个体化。通过有限采样策略和贝叶斯估计基于浓度-时间曲线下面积进行剂量调整比谷浓度更可靠。治疗药物监测和剂量调整可纳入常规移植后咨询,并应在紧急情况(如排斥反应、不良事件、依从性差、合用药物发生潜在药物相互作用的变化及其他情况)中予以考虑。

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