Tacrolimus Concentrations Measured in Excreted Bile in Liver Transplant Recipients: The STABILE Study

Abstract Purpose Tacrolimus (TAC) is the main immunosuppressive drug in liver transplantation. Despite intensive therapeutic drug monitoring (TDM) that relies on whole blood trough concentration (TAC blood ), 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 PBMC ) 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 bileC ) could be a relevant surrogate marker of its efficacy. Methods 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 bileC was measured. The correlation between TAC bileC and TAC PBMC as well as between TAC blood and TAC PBMC was assessed. The correlations between TAC bileC and liver graft function parameter or with occurrence of neurologic toxic effects were also evaluated. Findings Between May 2016 and April 2017, 41 patients were analyzed. TAC bileC was significantly correlated with TAC PBMC ( r  = 0.25, P  = 0.007). However, a better correlation was found between TAC PBMC and TAC blood ( r  = 0.53, P bileC 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 bileC 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). Implications TAC bileC is not a better surrogate maker of TAC activity than TAC blood . However, TAC bileC could help predict the occurrence of TAC toxic effects when a T-tube is inserted. ClinicalTrials.gov identifier: NCT02820259 .