Lessons From Routine Dose Adjustment of Tacrolimus in Renal Transplant Patients Based on Global Exposure

Objectives: Since 2007, a number of transplantation centers have been routinely using an expert system for tacrolimus (TAC) dose adjustment in kidney allograft recipients, based on PK modeling and Bayesian estimation for area-under-the-curve (AUC) determination. This has allowed the setting up of a large database of TAC pharmacokinetic profiles and AUC values, a part of which was analyzed here. Methods: We retrospectively studied 2030 requests posted by 21 different centers for routine TAC dose adjustment in 1000 different adult renal transplant patients (not enrolled in any kind of concentration-controlled clinical trial). For each request, the following information was obtained: time elapsed since transplantation, TAC daily dose, calculated AUC, and trough concentration (C-0). Results: The dose-standardized exposure to TAC significantly and progressively increased in the months after transplantation: from month (M) 1 to M9 C-0/dose increased from 2.33 to 3.44 mcg.L-1.mg(-1) and AUC/dose from 43.1 to 64.2 mcg.h(-1).L-1.mg(-1), respectively. On the contrary, in patients beyond the first year whose C-0 or AUC was in the target range, the odds of remaining in this range were high for a long time period, suggesting a low intrapatient variability in the stable phase. Regression analyses showed that the correlation between C-0 and AUC was better in the first 3-month period (r(2) = 0.76) than later on (r(2) <= 0.67). Using the regression equations obtained, AUC ranges corresponding to different applicable C-0 targets were calculated. Conclusions: From a large number of kidney graft recipients, we have estimated the relationships between C-0 and AUC, modeled the evolution of TAC exposure with time and defined AUC targets that could be useful to lead further controlled-concentration trials and improve routine TAC therapeutic drug monitoring.