Tacrolimus dose individualization in de novo patients after 10 years of experience in liver transplantation: pharmacokinetic considerations and patient pathophysiology

Aim: To determine how changes in tacrolimus (TAC) immunosuppression clinical practice, in the first 15 days post liver transplantation (LT) and across a decade, impact a clinical covariate - pharmacokinetic (PK) model, developed in data from 1998, thus testing its utility in dose individualization across time. Patient cohorts from 1998 (Reference: R-1998) and 2007 (Evaluation: E-2007) were compared. Methods: Analysis of monitoring observations (C-min and C-min/dose) and the biochemical variables aspartate aminotransferase (AST), hematocrit (HCT), albumin (ALB) and serum creatinine (SCr) was done for 0 - 3 and 4 - 15 days post transplantation (PT). The population PK model developed for R-1998 [1] was re-evaluated for the two cohorts. Results: Significant differences in R-1998 vs. E-2007 existed in C-min and C-min/dose and in covariates AST (as hepatic function marker) and SCr (as toxicity marker). E-2007 had lower levels of C-min and C-min/dose (1/CL), lower AST with faster recovery and lower variability in C-min/dose for similar dose. AST was a covariate on CL/F in the 0 3 day PT period. In 4 - 15 days PT for E-2007, low levels of HCT and ALB as CL/F predictors confirmed a subgroup with higher CL/F (23.8 1/h vs. 19.3 1/h). The R-1998 model's original structure was confirmed. Conclusions: Ten years of use of TAC shows gain in therapeutic targeting efficiency, due to improvement in LT methods, knowledge of the drug and consideration of PK steady state. The remaining uncertainty with TAC monitoring in LT can be resolved with application of PK principles combined with patients' idiosyncrasies in the model developed for TAC dose individualization in R-1998. The applicability of the model as nucleus in Bayes individualization remains intact across a decade.