Tacrolimus Predose Concentrations Do Not Predict the Risk of Acute Rejection After Renal Transplantation: A Pooled Analysis From Three Randomized-Controlled Clinical Trials

Abstract

Therapeutic drug monitoring (TDM) for tacrolimus (Tac)is universally applied. However, the concentration-effect relationship for Tac is poorly defined. This study investigated whether Tac concentrations are associated with acute rejection in kidney transplant recipients. Data from three large trials were pooled. We used univariate and multivariate analysis to investigate the relationship between biopsy-proven acute rejection (BPAR) and Tac predose concentration at five time points (day 3, 10 and 14, and month 1 and 6 after transplantation). A total of 136/1304 patients experienced BPAR, giving an overall incidence of 10.4%. We did not find any significant correlations between Tac predose concentrations and the incidence of BPAR at the different time points. In the multivariate analysis, only delayed graft function (DGF) and the use of induction therapy were independently correlated with BPAR, with an odds ratio of 2.7 [95% CI: 1.8-4.0; p < 0.001] for DGF and 0.66 [95% CI: 0.44-0.99; p = 0.049] for induction therapy. The other variables, including the Tac predose concentrations, were not statistically significantly associated with BPAR. We did not find an association between the Tac predose concentrations measured at five time points after kidney transplantation and the incidence of acute rejection occurring thereafter. Based on this study it is not possible to define the optimal target concentrations for Tac.

Standardization of LC-MS for Therapeutic Drug Monitoring of Tacrolimus

“…This level of standardization represents a major improvement over both immunoassays and laboratory-developed LC-MS tests for tacrolimus therapeutic drug monitoring and should ease the translation of results from clinical trials and consensus guidelines into routine clinical practice. Furthermore, an accurate and precise technique for monitoring tacrolimus may help to better define the concentration-effect relationship for this drug that has been ill-defined to date (2 ). We believe this to be the first study to demonstrate standardization of an LC-MS assay for tacrolimus across multiple laboratories, and it could provide a model for future studies that aim to quantify the impact of individual parameters that contribute to the variability in LC-MS assays.…”

“…Monitoring trough whole blood concentrations, the preferred specimen in clinical settings (1 ), is generally regarded as a good surrogate for tacrolimus exposure. Although dose adjustments critical to regulating the degree of immunosuppression are made, in part on the basis of laboratory results, precise therapeutic ranges have yet to be established (2 ). It is possible that the concentration-effect relationship for tacrolimus has not been better defined because of the variety of analytical methods for measuring tacrolimus in use today and the lack of their standardization and traceability to a single defined source.…”

Pharmacokinetic considerations related to therapeutic drug monitoring of tacrolimus in kidney transplant patients

“…In a recent study, data from three clinical trials were pooled (n = 1304) and analyzed. No correlation was found between the Tac C 0 measured at five time points (day 3, 10, and 14, and month 1 and 6 after transplantation) and the occurrence of acute rejection in the period thereafter, in the first posttransplant year [21].…”

“…Some clinicians have started to question the current reliance on C 0 when performing TDM of Tac, with instances of toxicity and rejection occurring when C 0 are within 'acceptable' ranges. Amongst the transplant professionals, there is an ongoing debate as to whether the Tac C 0 sufficiently predicts kidney transplant rejection (see below) [21].…”

“…In the past 20 years, there has been a substantial change in the target Tac concentration after kidney transplantation, with target concentrations as high as 20 ng/mL in the early 1990s, and with targets as low as 3-7 ng/mL after the publication of the Symphony-Elite study [3]. However, only few studies have compared different Tac concentration ranges and there is little support to promote the use of a specific therapeutic window and aim for certain target concentrations [21].…”