Service de Chirurgie Hépatobiliaire et Digestive, CHU Rennes, Rennes, France; Inserm, CIC 1414 (Centre d'Investigation Clinique de Rennes), Rennes, France; Faculté de Médecine, Université Rennes, Rennes, France.
Inserm, CIC 1414 (Centre d'Investigation Clinique de Rennes), Rennes, France; Faculté de Médecine, Université Rennes, Rennes, France; Department of Clinical and Biological Pharmacology and Pharmacovigilance, CHU Rennes, Rennes, France.
Clin Ther. 2018 Dec;40(12):2088-2098. doi: 10.1016/j.clinthera.2018.10.015. Epub 2018 Nov 19.
Tacrolimus (TAC) is the main immunosuppressive drug in liver transplantation. Despite intensive therapeutic drug monitoring (TDM) that relies on whole blood trough concentration (TAC), patients still present with acute cellular rejection or TAC-related toxic effects with concentrations within the therapeutic range. TAC concentration in peripheral blood mononuclear cells (TAC) is considered as an efficient surrogate marker of TAC efficacy. However, it is still not applicable in daily practice. New TDM methods are therefore needed, especially during the early postoperative period. TAC is metabolized in the liver and eliminated through biliary excretion. We therefore hypothesised that TAC concentration measured in excreted bile (TAC) could be a relevant surrogate marker of its efficacy.
The Therapeutic Drug Monitoring of Tacrolimus Biliary Concentrations for Liver-Transplanted Patients (STABILE) study is a prospective monocentric trial. During the 7 first days after TAC therapy initiation, TAC was measured. The correlation between TAC and TAC as well as between TAC and TAC was assessed. The correlations between TAC and liver graft function parameter or with occurrence of neurologic toxic effects were also evaluated.
Between May 2016 and April 2017, 41 patients were analyzed. TAC was significantly correlated with TAC (r = 0.25, P = 0.007). However, a better correlation was found between TAC and TAC (r = 0.53, P < 0.001) and was confirmed in multivariate analysis. However, only TAC was significantly correlated with liver graft function, such as factor V (r = 0.40, P = 0.009) or bilirubin level (r = 0.21, P = 0.01), and significantly lower in patients presenting with neurologic toxic effects (P < 0.001). Receiver operating characteristic curve analysis found that a TAC level lower than 0.20 ng/mL on day 2 after TAC therapy initiation was a good predictive marker of occurrence of neurotoxic effects (AUC = 0.81).
TAC is not a better surrogate maker of TAC activity than TAC. However, TAC could help predict the occurrence of TAC toxic effects when a T-tube is inserted. ClinicalTrials.gov identifier: NCT02820259.
他克莫司（TAC）是肝移植中主要的免疫抑制剂。尽管通过全血谷浓度（TAC）进行了强化治疗药物监测（TDM），但仍有患者出现急性细胞排斥反应或 TAC 相关毒性作用，而此时 TAC 浓度处于治疗范围内。外周血单个核细胞中的 TAC 浓度（TAC）被认为是 TAC 疗效的有效替代标志物。然而，它在实际应用中仍然不可行。因此，需要新的 TDM 方法，特别是在术后早期。TAC 在肝脏中代谢并通过胆汁排泄消除。因此，我们假设从胆汁中测量的 TAC 浓度（TAC）可能是其疗效的一个相关替代标志物。
肝移植患者他克莫司胆汁浓度的治疗药物监测（STABILE）研究是一项前瞻性单中心试验。在开始 TAC 治疗后的前 7 天内，测量了 TAC。评估了 TAC 与 TAC 以及 TAC 与 TAC 之间的相关性。还评估了 TAC 与肝移植物功能参数之间或与发生神经毒性作用之间的相关性。
2016 年 5 月至 2017 年 4 月期间，分析了 41 名患者。TAC 与 TAC 显著相关（r=0.25，P=0.007）。然而，TAC 与 TAC 之间的相关性更好（r=0.53，P<0.001），并在多变量分析中得到证实。然而，只有 TAC 与肝移植物功能相关，如因子 V（r=0.40，P=0.009）或胆红素水平（r=0.21，P=0.01），并且在发生神经毒性作用的患者中显著降低（P<0.001）。接受者操作特征曲线分析发现，TAC 治疗开始后第 2 天 TAC 水平低于 0.20ng/mL 是发生神经毒性作用的良好预测标志物（AUC=0.81）。
TAC 不是 TAC 活性的更好替代标志物。然而，当插入 T 管时，TAC 可帮助预测 TAC 毒性作用的发生。临床试验.gov 标识符：NCT02820259。
