Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, Michigan, USA.
Pharmacotherapy. 2021 Aug;41(8):649-657. doi: 10.1002/phar.2601. Epub 2021 Jul 1.
This study investigated the effect of CYP3A5 phenotype on time in therapeutic range (TTR) of tacrolimus post-transplant in pediatric patients.
This retrospective study assessed medical records of pediatric kidney and heart recipients with available CYP3A5 genotype for tacrolimus dosing, troughs, and the clinical events (biopsy-proven acute rejection [BPAR] and de novo donor-specific antibodies [dnDSA]).
The primary outcome, mean TTR in the first 90 days post-transplant, was 9.0% (95% CI: -16.1, -1.9) lower in CYP3A5 expressers (p = 0.014) when adjusting for time to therapeutic concentration and organ type. There was no difference between CYP3A5 phenotypes in time to the first clinical event using TTR during the first 90 days. When applying TTR over the first year, there was a significant difference in event-free survival (EFS) which was 50.0% for CYP3A5 expressers/TTR < 35%, 45.5% for expressers/TTR ≥ 35%, 38.1% for nonexpressers/TTR < 35%, and 72.9% for nonexpressers/TTR ≥ 35% (log-rank p = 0.03). A post hoc analysis of EFS identified CYP3A5 expressers had lower EFS compared to nonexpressers in patients with TTR ≥ 35% (p = 0.04) but no difference among patients with TTR < 35% (p = 0.6).
The relationship between TTR and CYP3A5 phenotype suggests that achieving a TTR ≥ 35% during the first year may be a modifiable factor to attenuate the risk of BPAR and dnDSA.
本研究旨在探讨 CYP3A5 表型对儿童患者移植后他克莫司治疗窗内时间（TTR）的影响。
本回顾性研究评估了具有可用于他克莫司剂量、谷值和临床事件（经活检证实的急性排斥反应[BPAR]和新供体特异性抗体[dnDSA]）的 CYP3A5 基因型的儿科肾和心脏受者的病历。
主要结局指标，即移植后 90 天内的平均 TTR，在 CYP3A5 表达者中降低了 9.0%（95%CI：-16.1，-1.9）（p=0.014），在调整达到治疗浓度的时间和器官类型后。在 90 天内，CYP3A5 表型之间在第一个临床事件发生时间方面没有差异。当应用第一年的 TTR 时，无事件生存（EFS）有显著差异，CYP3A5 表达者/TTR<35%为 50.0%，表达者/TTR≥35%为 45.5%，非表达者/TTR<35%为 38.1%，非表达者/TTR≥35%为 72.9%（对数秩检验 p=0.03）。EFS 的事后分析表明，在 TTR≥35%的患者中，CYP3A5 表达者的 EFS 低于非表达者（p=0.04），但在 TTR<35%的患者中无差异（p=0.6）。
TTR 与 CYP3A5 表型之间的关系表明，在第一年达到 TTR≥35%可能是一个可调节的因素，可以降低 BPAR 和 dnDSA 的风险。
