title: Pathophysiological idiosyncrasies and pharmacokinetic realities may interfere with tacrolimus dose titration in liver transplantation.
abstract: OBJECTIVE
  To explore the main factors that make it difficult to empirically monitor tacrolimus (TAC) in the early period post-liver transplantation (LTx), with a specific focus on those aspects related to patient idiosyncrasy and clinical status as well as to the pharmacokinetic (PK) assumptions on which drug individualization in clinical practice is based.
  
  
  METHODS
  Retrospective monitoring data from 75 de novo liver transplant patients treated with twice daily with TAC and followed for up to 15 days were analyzed. An extensive battery of laboratory measurements were available. Dose adjustment was performed empirically using trough levels (C(min)). The population was separated into two major background groups according to low or high values of aspartate aminotransferase (AST) (Group 1 and 2, respectively) based on AST measurements made during the first 4 days post-LTx. Each of these two major groups was then further subdivided into two subgroups based on elevated (Groups 1A, 2A) or reduced (Groups 1B, 2B) combined albumin (cut-off 2.5 g/dl) and hematocrit (cut-off 28%).
  
  
  RESULTS
  The C(min)/Dose ratio [inversely proportional to systemic clearance (CL)] had a variability [coefficient of variation (CV) >80%) that was incongruently higher for the ratio than for C(min) and Dose separately. This was attributed to most patients not being at steady state or physiologically stable in the early post-LTx period. Group 1 patients were more predictable than Group 2 patients, who were responsible for the variability in the ratio. C(min) was lower in the reduced ALB and HCT patient groups when AST conditions were similar (1A vs. 1B and 2A vs. 2B), likely due to increased TAC metabolic clearance (reduced C(min)/Dose). This situation existed for two periods: 0-15 days post-LTx and 4-15 days post-LTx observations. Group 2A patients were the main source of the paradoxical variability in C(min)/Dose (higher ratio of 2.7; CV = 100%), suggesting a lower clearance and difficulty in the recovery of stability. In contrast, Group 2B patients had the lower ratio (1.4; 47%) but required the highest number of dose adjustments as the variability was hard to identify clinically. Group 1A patients were the most predictable empirically. When observations from 15 new patients who entered the clinic in 2007 and 2008 were used for the analysis, the same sub-groups existed in the same proportions in both years.
  
  
  CONCLUSIONS
  The difficulty in empirical dose adjustment of TAC is associated to the inevitable non-fulfillment of PK assumptions early post-LTx and also to the inherent complexity of the clinical condition, leading to increased uncertainty for the clinician regarding dose selection. Identifying these sub-categories provides a rational means of classifying patients akin to a phenotype. The complexity of the kinetics in LTx and TAC treatment does not invalidate C(min) as a biomarker, but a Bayes algorithm including a full PK structure and these covariates would be optimal.
authors.affiliation: Department of Pharmacology, School of Medicine, Universidad del Pais Vasco, Leioa, Spain.
authors.forename: Itziar
authors.initials: I
authors.lastname: Oteo
authors.forename: John C
authors.initials: JC
authors.lastname: Lukas
authors.forename: Nerea
authors.initials: N
authors.lastname: Leal
authors.forename: Elena
authors.initials: E
authors.lastname: Suarez
authors.forename: Andres
authors.initials: A
authors.lastname: Valdivieso
authors.forename: Mikel
authors.initials: M
authors.lastname: Gastaca
authors.forename: Jorge Ortiz
authors.initials: JO
authors.lastname: de Urbina
authors.forename: Rosario
authors.initials: R
authors.lastname: Calvo
mesh_terms: D000328:Adult; D019540:Area Under Curve; D004305:Dose-Response Relationship, Drug; D016903:Drug Monitoring; D006084:Graft Rejection / Q000517:prevention & control; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008111:Liver Function Tests; D016031:Liver Transplantation; D012044:Regression Analysis; D012189:Retrospective Studies; D016559:Tacrolimus / Q000008:administration & dosage / Q000493:pharmacokinetics*
chemical_list: D007166:Immunosuppressive Agents; D016559:Tacrolimus