Ten years ago, a consensus report on the optimization of tacrolimus was published in this journal. In 2017, the Immunosuppressive Drugs Scientific Committee of the International Association of Therapeutic Drug Monitoring and Clinical Toxicity (IATDMCT) decided to issue an updated consensus report considering the most relevant advances in tacrolimus pharmacokinetics (PK), pharmacogenetics (PG), pharmacodynamics, and immunologic biomarkers, with the aim to provide analytical and drug-exposure recommendations to assist TDM professionals and clinicians to individualize tacrolimus TDM and treatment. The consensus is based on in-depth literature searches regarding each topic that is addressed in this document. Thirty-seven international experts in the field of TDM of tacrolimus as well as its PG and biomarkers contributed to the drafting of sections most relevant for their expertise. Whenever applicable, the quality of evidence and the strength of recommendations were graded according to a published grading guide. After iterated editing, the final version of the complete document was approved by all authors. For each category of solid organ and stem cell transplantation, the current state of PK monitoring is discussed and the specific targets of tacrolimus trough concentrations (predose sample C0) are presented for subgroups of patients along with the grading of these recommendations. In addition, tacrolimus area under the concentration–time curve determination is proposed as the best TDM option early after transplantation, at the time of immunosuppression minimization, for special populations, and specific clinical situations. For indications other than transplantation, the potentially effective tacrolimus concentrations in systemic treatment are discussed without formal grading. The importance of consistency, calibration, proficiency testing, and the requirement for standardization and need for traceability and reference materials is highlighted. The status for alternative approaches for tacrolimus TDM is presented including dried blood spots, volumetric absorptive microsampling, and the development of intracellular measurements of tacrolimus. The association between CYP3A5 genotype and tacrolimus dose requirement is consistent (Grading A I). So far, pharmacodynamic and immunologic biomarkers have not entered routine monitoring, but determination of residual nuclear factor of activated T cells–regulated gene expression supports the identification of renal transplant recipients at risk of rejection, infections, and malignancy (B II). In addition, monitoring intracellular T-cell IFN-g production can help to identify kidney and liver transplant recipients at high risk of acute rejection (B II) and select good candidates for immunosuppression minimization (B II). Although cell-free DNA seems a promising biomarker of acute donor injury and to assess the minimally effective C0 of tacrolimus, multicenter prospective interventional studies are required to better evaluate its clinical utility in solid organ transplantation. Population PK models including CYP3A5 and CYP3A4 genotypes will be considered to guide initial tacrolimus dosing. Future studies should investigate the clinical benefit of time-to-event models to better evaluate biomarkers as predictive of personal response, the risk of rejection, and graft outcome. The Expert Committee concludes that considerable advances in the different fields of tacrolimus monitoring have been achieved during this last decade. Continued efforts should focus on the opportunities to implement in clinical routine the combination of new standardized PK approaches with PG, and valid biomarkers to further personalize tacrolimus therapy and to improve long-term outcomes for treated patients.
When mycophenolic acid (MPA) was originally marketed for immunosuppressive therapy, fixed doses were recommended by the manufacturer. Awareness of the potential for a more personalized dosing has led to development of methods to estimate MPA area under the curve based on the measurement of drug concentrations in only a few samples. This approach is feasible in the clinical routine and has proven successful in terms of correlation with outcome. However, the search for superior correlates has continued, and numerous studies in search of biomarkers that could better predict the perfect dosage for the individual patient have been published. As it was considered timely for an updated and
Background: Therapeutic drug monitoring is standard practice for the immunosuppressant tacrolimus (Tac). Venous blood sampling at outpatient clinics is time-consuming and impractical with regard to obtaining trough concentrations on clinical visit days. Home-based blood sampling may be patient friendly and pave the way for limited sampling strategies for the prediction of total drug exposure. The aim was to establish a Tac assay for dried capillary microsamples, ensuring reliable measurements during the full dose interval in renal transplant recipients. Methods: An assay based on volumetric absorptive microsampling and liquid chromatography tandem mass spectrometry was validated. The agreement between capillary microsamples and liquid venous samples was investigated in stable renal recipients on twice-daily Tac dosing. Sampling throughout the 12-hour dose interval was examined at 2 separate days, at least 1 week apart, for each participant. Two sets of samples were obtained at each time point, one delivered directly to the laboratory and one sent through mail. Results: Twenty-seven renal transplant recipients were included, of whom 26 were investigated twice. Tac was efficiently extracted from the dried microsamples (mean recovery 94%–103%). The between-series mean accuracy was 88%–98% with coefficients of variation ≤5.0% (≤11% at the lower limit of quantification), measurement range 0.70–60 mcg/L. The mean difference between parallel microsamples was 5%–7%. Overall, the mean differences between dried microsamples and liquid samples were −3.1% when mailed (n = 679) and −4.2% when directly delivered (n = 682). Less than 8% were outside ±20%. The microsamples were stable for 1 month at ambient temperature. Conclusions: The microsample method demonstrated acceptable performance. Tac concentrations can be reliably quantified throughout the dose interval by using volumetric absorptive microsampling in renal transplant recipients, and the results are not influenced by postal shipment.
Knowledge of changes in IMPDH 1 and 2 expression after transplantation and initiation of immunosuppression is important considering the action of MPA on IMPDH and the potential for pharmacodynamic monitoring of MPA by measuring IMPDH activity. The expression of IMPDH2 in CD4+ cells pretransplant may be an indicator of immune activation.
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