Tacrolimus (TAC) is the main immunosuppressive drug in liver transplantation. Despite intensive therapeutic drug monitoring (TDM) that relies on whole blood trough concentration (TACblood), 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 (TACPBMC) 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 (TACbileC) 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, TACbileC was measured. The correlation between TACbileC and TACPBMC as well as between TACblood and TACPBMC was assessed. The correlations between TACbileC 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. TACbileC was significantly correlated with TACPBMC (r = 0.25, P = 0.007). However, a better correlation was found between TACPBMC and TACblood (r = 0.53, P < 0.001) and was confirmed in multivariate analysis. However, only TACbileC 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 TACbileC 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).TACbileC is not a better surrogate maker of TAC activity than TACblood. However, TACbileC could help predict the occurrence of TAC toxic effects when a T-tube is inserted. ClinicalTrials.gov identifier: NCT02820259.

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