Tacrolimus-related adverse effects in liver transplant recipients: its association with trough concentrations.

Background: Tacrolimus is an important immunosuppressant administered to patients following liver transplantation (LT), with a recommended trough concentration of 8 to 11 ng/mL to prevent allograft rejection. We retrospectively examined our data to identify the tacrolimus trough concentration that combined efficacy with minimal adverse effects.

Methods: The case records of LT recipients, who were nondiabetic, nonhypertensive, and with normal renal parameters prior to LT were retrospectively examined for acute cellular rejection (ACR) episodes and three major adverse effects of tacrolimus, i.e. neurotoxicity, nephrotoxicity, and new onset diabetes mellitus (NODM).

Results: Thirty-two LT recipients fulfilled the criteria for the study. The mean (±SD) tacrolimus level for the 290 troughs (after 10 days) was 8.5 ± 3.8 ng/mL. At 10 days, 1 month, 3 months, and 6 months, the trough values were 7.3 ± 2.9, 9.7 ± 3.4, 7.9 ± 3.3, and 7.6 ± 2.6 ng/mL, respectively. The mean time taken for stabilization of the blood pressure and biochemical parameters was 7 ± 2 days. Overall, a trough window with the least adverse effect was 7 to 7.9 ng/mL. Neurotoxicity was least in the trough range 5 to <8 ng/mL. Symptoms included headache in four, tremors in three, seizure in one, confusion and psychosis in two, and combination in three. Nephrotoxicity was least in trough 8 to <11 ng/mL. One patient progressed to chronic kidney disease at 6 months. NODM was present in 11 % to 18 % across the various trough range, including the extremes (mean trough level, 8.4 ± 4.4 ng/dL). At 6 months, five recipients were on treatment for NODM. Three recipients developed ACR, two within the first month and one at 7 weeks. The trough levels were 8.5, 9, 15.2 ng/mL, respectively. All recovered with three pulse doses of methylprednisolone.

Conclusion: Tacrolimus concentration of 5 to <8 ng/mL was associated with least overall toxicity, neurotoxicity, and ACR.