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Therapeutic Drug Monitoring of Tacrolimus-Personalized Therapy

Second Consensus Report

Brunet, Mercè, PharmD, PhD1; van Gelder, Teun, MD, PhD2; Åsberg, Anders, PhD3; Haufroid, Vincent, PharmD, PhD4,5; Hesselink, Dennis A., MD, PhD6; Langman, Loralie, PhD7; Lemaitre, Florian, PharmD, PhD8; Marquet, Pierre, MD, PhD9; Seger, Christoph, PhD10; Shipkova, Maria, MD11; Vinks, Alexander, PharmD, PhD12,13; Wallemacq, Pierre, PharmD, PhD14; Wieland, Eberhard, MD11; Woillard, Jean Baptiste, PharmD, PhD15; Barten, Markus J., MD16; Budde, Klemens, MD, PhD17; Colom, Helena, PharmD, PhD18; Dieterlen, Maja-Theresa, MD19; Elens, Laure, PhD20; Johnson-Davis, Kamisha L., PhD21; Kunicki, Paweł K., PhD22,23; MacPhee, Iain, MD24; Masuda, Satohiro, PhD25; Mathew, Binu S., MD26; Millán, Olga, PhD1; Mizuno, Tomoyuki, MD12,13; Moes, Dirk-Jan A. R., PharmD, PhD27; Monchaud, Caroline, PharmD, PhD15; Noceti, Ofelia, PharmD, PhD28; Pawinski, Tomasz, PhD23; Picard, Nicolas, PharmD, PhD15; van Schaik, Ron, MD29; Sommerer, Claudia, MD30; Vethe, Nils Tore, PhD31; de Winter, Brenda, PharmD, PhD32; Christians, Uwe, MD, PhD33; Bergan, Stein, PhD31

doi: 10.1097/FTD.0000000000000640
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Abstract: 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.

1Pharmacology and Toxicology Laboratory, Biochemistry and Molecular Genetics Department, Biomedical Diagnostic Center, Hospital Clinic of Barcelona, University of Barcelona, IDIBAPS, CIBERehd, Barcelona, Spain;

2Department of Internal Medicine and Hospital Pharmacy, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands;

3Department of Transplantation Medicine, Section of Nephrology, Oslo University Hospital-Rikshospitalet, Oslo, Norway;

4Louvain Center for Toxicology and Applied Pharmacology (LTAP), Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium;

5Department of Clinical Chemistry, Cliniques Universitaires Saint-Luc, Brussels, Belgium;

6Department of Internal Medicine, Division of Nephrology and Transplantation, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands;

7Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota;

8Rennes University Hospital & INSERM, Department of Clinical and Biological Pharmacology and Pharmacovigilance, Pharmacoepidemiology and Drug Information Center, Clinical Investigation Center CIC-P 1414, Rennes, France;

9INSERM, University of Limoges, CHU Limoges, IPPRITT, U1248, Limoges, France;

10Division of Mass Spectrometry and Chromatography, Institute of Medical and Chemical Laboratory Diagnostics (ZIMCL), University Hospital Innsbruck, Innsbruck, Austria;

11SYNLAB Holding Germany GmbH, Competence Center for Therapeutic Drug Monitoring, MVZ Leinfelden-Echterdingen GmbH, Stuttgart, Germany;

12Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio;

13Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio;

14Clinical Chemistry Department, Cliniques Universitaires Saint-Luc, Center for Toxicology and Applied Pharmacology, Université Catholique de Louvain, Brussels, Belgium;

15Department of Pharmacology and Toxicology, CHU Limoges, Limoges, France;

16Department of Cardiovascular Surgery, University Heart Center Hamburg, Hamburg, Germany;

17Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, Berlin, Germany;

18Pharmacy and Pharmaceutical Technology and Physical Chemistry Department, University of Barcelona, Barcelona, Spain;

19Department for Cardiac Surgery, Heart Center Leipzig, University of Leipzig, Leipzig, Germany;

20Louvain Drug Research Institute, Integrated PharmacoMetrics, PharmacoGenomics and PharmacoKinetics, Université Catholique de Louvain, Brussels, Belgium;

21Department of Pathology, University of Utah Health Sciences Center, Salt Lake City, Utah;

22Clinical Pharmacology Unit, Department of Medical Biology, Institute of Cardiology, Warsaw, Poland;

23Department of Drug Chemistry, Faculty of Pharmacy, Medical University of Warsaw, Warsaw, Poland;

24St George's Hospital, London, United Kingdom;

25Department of Pharmacy, Kyushu University Hospital, Fukuoka, Japan;

26Department of Pharmacology and Clinical Pharmacology, Christian Medical College, Vellore, India;

27Department of Clinical Pharmacy & Toxicology, Leiden University Medical Center, Leiden, the Netherlands;

28National Center for Liver Transplantation and Liver Diseases, Uruguay, South America;

29Department of Clinical Chemistry, Erasmus University Medical Center, Rotterdam, the Netherlands;

30Department of Nephrology, University of Heidelberg, Heidelberg, Germany;

31Department of Pharmacology, Oslo University Hospital, Oslo, Norway;

32Department of Hospital Pharmacy, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands; and

33iC42 Clinical Research and Development, Department of Anesthesiology, University of Colorado Denver Anschutz Medical Campus, Aurora, Colorado.

Correspondence: Mercè Brunet, PharmD, PhD, Pharmacology and Toxicology Laboratory, Biochemistry and Molecular Genetics Department, Biomedical Diagnostic Center, Hospital Clinic of Barcelona, University of Barcelona, Villarroel 170, 08036 Barcelona, Spain (e-mail: mbrunet@clinic.cat).

M. Brunet has received grant support from Chiesi as well as lecture and consulting fees from Astellas Pharma. T. van Gelder has received lecture fees from Roche, Chiesi and Astellas Pharma, in addition to consulting fees from Roche Diagnostics, Vitaeris, Astellas and Novartis. Teun van Gelder has received grants for clinical trials from Astellas Pharma and from Chiesi. D. A. Hesselink has received lecture and consulting fees, as well as grant support from Astellas Pharma and Chiesi Pharmaceutici SpA. K. Budde has received research funds and/or honoraria from Alexion, Astellas, Bristol-Myers Squibb, Chiesi, Fresenius, Genentech, Hexal, Novartis, Otsuka, Pfizer, Roche, Sandoz, Siemens, and Veloxis Pharma. F. Lemaitre has received research grants from Astellas, Research grant and congress invitation from Sandoz, Speaker fees from Chiesi. I. MacPhee has received research funding from Astellas and Chiesi and honoraria from Astellas, Sandoz and Chiesi. P. Marquet has received contracts with and research funds from Astellas, Chiesi and Sandoz. S. Masuda has received payment for lectures: Astellas, Chugai, Novartis, Siemens, Roche Diagnostics, Sekisui Medical. J. B. Woillard has received honoraria from Chiesi. The remaining authors declare no conflict of interest.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.drug-monitoring.com).

Received December 12, 2018

Accepted March 21, 2019

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