Department of Pharmacy Practice, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, Thailand.
Br J Clin Pharmacol. 2024 Feb;90(2):406-426. doi: 10.1111/bcp.15909. Epub 2023 Oct 4.
This study aimed to provide up-to-date information on paediatric population pharmacokinetic models of tacrolimus and to identify factors influencing tacrolimus pharmacokinetic variability.
Systematic searches in the Web of Science, PubMed, Scopus, Science Direct, Cochrane, EMBASE databases and reference lists of articles were conducted from inception to March 2023. All population pharmacokinetic studies of tacrolimus using nonlinear mixed-effect modelling in paediatric solid organ transplant patients were included.
Of the 21 studies reviewed, 62% developed from liver transplant recipients and 33% from kidney transplant recipients. Most studies used a 1-compartment model to describe tacrolimus pharmacokinetics. Body weight was a significant predictor for tacrolimus volume of distribution (Vd/F). The estimated Vd/F for 1-compartment models ranged from 20 to 1890 L, whereas the peripheral volume of distribution (Vp/F) for 2-compartment models was between 290 and 1520 L. Body weight, days post-transplant, CYP3A5 genotype or haematocrit were frequently reported as significant predictors of tacrolimus clearance. The estimated apparent clearance values range between 0.12 and 2.18 L/h/kg, with inter-individual variability from 13.5 to 110.0%. Only 29% of the studies assessed the generalizability of the models with external validation.
This review highlights the potential factors, modelling approaches and validation methods that impact tacrolimus pharmacokinetics in a paediatric population. The clinician could predict tacrolimus clearance based on body weight, CYP3A5 genotype, days post-transplant or haematocrit. Further research is required to determine the relationship between pharmacogenetics and tacrolimus pharmacodynamics in paediatric patients and confirm the applicability of nonlinear kinetics in this population.
本研究旨在提供有关他克莫司在儿科人群中的药代动力学模型的最新信息，并确定影响他克莫司药代动力学变异性的因素。
系统检索了 Web of Science、PubMed、Scopus、Science Direct、Cochrane、EMBASE 数据库以及文章的参考文献列表，检索时间截至 2023 年 3 月。所有使用非线性混合效应模型进行的关于儿童实体器官移植患者他克莫司群体药代动力学研究均被纳入。
在 21 项综述的研究中，62%来自于肝移植受者，33%来自于肾移植受者。大多数研究采用 1 室模型来描述他克莫司的药代动力学。体重是他克莫司分布容积（Vd/F）的重要预测因素。1 室模型估计的 Vd/F 范围为 20 至 1890 L，而 2 室模型的外周分布容积（Vp/F）为 290 至 1520 L。体重、移植后天数、CYP3A5 基因型或红细胞压积经常被报道为他克莫司清除率的重要预测因素。估计的表观清除率值在 0.12 至 2.18 L/h/kg 之间，个体间变异性为 13.5%至 110.0%。只有 29%的研究通过外部验证评估了模型的可推广性。
本综述强调了影响儿科人群中他克莫司药代动力学的潜在因素、建模方法和验证方法。临床医生可以根据体重、CYP3A5 基因型、移植后天数或红细胞压积预测他克莫司清除率。需要进一步研究来确定儿童患者中药物遗传学与他克莫司药效学之间的关系，并确认非线性动力学在该人群中的适用性。
