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

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 < 0.001) and was confirmed in multivariate analysis. However, only TAC _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 < 0.001). Receiver operating characteristic curve analysis found that a TAC _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.
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