High intrapatient variability of tacrolimus exposure associated with poorer outcomes in liver transplantation

Tacrolimus (TAC) is a dose-dependent immunosuppressor with considerable intrapatient variability (IPV) in its pharmacokinetics. The aim of this work is to ascertain the association between TAC IPV at 6 months after liver transplantation (LT) and patient outcome. This single-center cohort study retrospectively analyzed adult patients who underwent transplantation from 2015 to 2019 who survived the first 6 months with a functioning graft. The primary end point was the patient's probability of death and the secondary outcome was the loss of renal function between month 6 and the last follow-up. TAC IPV was estimated by calculating the coefficient of variation (CV) of the dose-corrected concentration (C/D) between the third and sixth months post-LT. Of the 140 patients who underwent LT included in the study, the low-variability group (C/D CV < 27%) comprised 105 patients and the high-variability group (C/D CV ≥ 27%) 35 patients. One-, 3-, and 5-year patient survival rates were 100%, 82%, and 72% in the high-variability group versus 100%, 97%, and 93% in the low-variability group, respectively (p = 0.005). Moreover, significant impaired renal function was observed in the high-variability group at 1 year (69 ± 16 ml/min/1.73 m 2 vs. 78 ± 16 ml/min/1.73 m 2, p = 0.004) and at 2 years post-LT (69 ± 17 ml/min/1.73 m 2 vs. 77 ± 15 ml/min/1.73 m 2, p = 0.03). High C/D CV 3-6 months remained independently associated with worse survival (hazard ratio = 3.57, 95% CI = 1.32-9.67, p = 0.012) and loss of renal function (odds ratio = 3.47, 95% CI = 1.30-9.20, p = 0.01). Therefore, high IPV between the third and sixth months appears to be an early and independent predictor of patients with poorer liver transplant outcomes.