A pharmacodynamic investigation of tacrolimus in pediatric liver transplantation

Although monitoring of tacrolimus blood concentrations is standard clinical practice following liver transplantation, a greater understanding of the relationship between trough concentrations and clinical outcome is required. The aim of this study was to perform a pharmacodynamic investigation of tacrolimus in pediatric liver transplant recipients. A retrospective analysis was performed on 35 pediatric liver recipients who received oral tacrolimus as the primary immunosuppressant. Outcome data were recorded corresponding to the times that tacrolimus trough concentrations had been determined (using a validated high-performance liquid chromatography-tandem mass spectrometry assay). A Mann-Whitney rank sum test was used to investigate differences between median concentrations at which drug toxicity, infection, and organ rejection did and did not occur. Outcome data and trough concentrations were recorded from the immediate post-transplant time to over 3 years (656 concentration-effect measures). Seventy one percent of data was obtained after the first 90 days post-transplant. Patients were identified as having experienced hypomagnesemia (20), hypertension (14), hyperkalemia (12), infection (11), nephrotoxicity (8), diarrhea (6), hyperglycemia (3), neurotoxicity(3), and rejection (3) during retrospective follow-up. Median trough concentrations were significantly higher (P <.05) at times patients experienced tacrolimus toxicity compared to no toxicity for nephrotoxicity (11.8 vs. 6.1 ng/mL) and neurotoxicity (15.1 vs. 6.2 ng/mL) and at times when patients suffered from diarrhea (8.9 vs. 6.0 ng/mL). No significant difference could be found between median trough concentrations at which hypertension, hyperkalemia, hyperglycemia, infection and organ rejection did and did not occur. A statistically significant relationship exists between some tacrolimus toxicities and tacrolimus trough concentrations. To minimize toxicity in the later post-transplant period, we propose a target trough tacrolimus concentration of 6 ng/mL.