Cancer Therapies, Stem Cell Medicine, Murdoch Children's Research Institute, Parkville, Melbourne, VIC, Australia.
Department of Paediatrics, The University of Melbourne, Parkville, Melbourne, VIC, Australia.
Br J Clin Pharmacol. 2024 Nov;90(11):2724-2741. doi: 10.1111/bcp.16203. Epub 2024 Aug 15.
Tacrolimus, a calcineurin inhibitor, is a highly effective immunosuppressant used in solid organ transplantation (SOT). However, it is characterized by a narrow therapeutic range and high inter-patient variability in pharmacokinetics. Standard weight-based dosing followed by empiric dose titration is suboptimal in controlling drug concentrations, increasing risk of rejection or toxicity, particularly in the initial months post transplantation. This review explores the potential of combined pre-transplant genotyping and pharmacokinetic (PK) modelling to improve tacrolimus dosing in paediatric SOT recipients. A systematic search of Medline, Embase and Cochrane databases identified studies published between March 2013 and March 2023 that investigated genotype- and PK model-informed tacrolimus dosing in children post-SOT. The Newcastle-Ottawa Scale assessed study quality. Seven studies encompassing paediatric kidney, heart, liver and lung transplants reported using genotype and model-informed dosing. A combination of clinical and genetic factors significantly impacts tacrolimus clearance and thus initial dose recommendation. Body size, transplant organ and co-medications were consistently important, while either time post-transplant or haematocrit emerged in some studies. Several models were identified, however, with limitations evident in some and with absence of evidence for their effectiveness in optimizing initial and subsequent dosing. This review highlights the development of PK models in paediatric SOT that integrate genotype and clinical covariates to personalize early tacrolimus dosing. While promising, prospective studies are needed to validate and confirm their effectiveness in improving time to therapeutic concentrations and reducing under- or overexposure. This approach has the potential to optimize tacrolimus therapy in paediatric SOT, thereby improving outcomes.
他克莫司是一种钙调神经磷酸酶抑制剂，是实体器官移植（SOT）中非常有效的免疫抑制剂。然而，它的治疗范围较窄，药代动力学在患者间存在较大差异。标准的基于体重的剂量方案随后进行经验性剂量滴定，在控制药物浓度方面并不理想，增加了排斥反应或毒性的风险，尤其是在移植后最初几个月。这篇综述探讨了联合移植前基因分型和药代动力学（PK）建模以改善儿科 SOT 受者他克莫司给药的潜力。通过对 Medline、Embase 和 Cochrane 数据库进行系统搜索，确定了 2013 年 3 月至 2023 年 3 月期间发表的研究，这些研究调查了基因分型和 PK 模型指导的 SOT 后儿童他克莫司给药。纽卡斯尔-渥太华量表评估了研究质量。有 7 项研究涵盖了儿科肾、心、肝和肺移植，报告了使用基因分型和模型指导的给药。临床和遗传因素的结合显著影响他克莫司的清除率，从而影响初始剂量建议。身体大小、移植器官和合并用药始终是重要因素，而有些研究则发现时间或红细胞压积（Hct）也很重要。确定了几种模型，但一些模型存在局限性，有些模型缺乏有效性证据来优化初始和后续剂量。这篇综述强调了儿科 SOT 中 PK 模型的发展，这些模型整合了基因分型和临床协变量，以实现早期他克莫司给药的个体化。虽然有希望，但需要前瞻性研究来验证和确认其在改善治疗浓度时间和减少药物暴露不足或过量方面的有效性。这种方法有可能优化儿科 SOT 中的他克莫司治疗，从而改善结果。
