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Barcelona Consensus on Biomarker-Based Immunosuppressive Drugs Management in Solid Organ Transplantation

Brunet, Mercè PhD; Shipkova, Maria MD; van Gelder, Teun MD, PhD; Wieland, Eberhard MD; Sommerer, Claudia MD; Budde, Klemens MD, PhD; Haufroid, Vincent PharmD, PhD; Christians, Uwe MD, PhD; López-Hoyos, Marcos MD, PhD; Barten, Markus J. MD; Bergan, Stein PhD; Picard, Nicolas PharmD, PhD; Millán López, Olga PhD; Marquet, Pierre MD, PhD; Hesselink, Dennis A. MD, PhD; Noceti, Ofelia PharmD, PhD; Pawinski, Tomasz MD; Wallemacq, Pierre PharmD, PhD; Oellerich, Michael MD

Therapeutic Drug Monitoring: April 2016 - Volume 38 - Issue - p S1–S20
doi: 10.1097/FTD.0000000000000287
Review Article

Abstract: With current treatment regimens, a relatively high proportion of transplant recipients experience underimmunosuppression or overimmunosuppression. Recently, several promising biomarkers have been identified for determining patient alloreactivity, which help in assessing the risk of rejection and personal response to the drug; others correlate with graft dysfunction and clinical outcome, offering a realistic opportunity for personalized immunosuppression. This consensus document aims to help tailor immunosuppression to the needs of the individual patient. It examines current knowledge on biomarkers associated with patient risk stratification and immunosuppression requirements that have been generally accepted as promising. It is based on a comprehensive review of the literature and the expert opinion of the Biomarker Working Group of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology. The quality of evidence was systematically weighted, and the strength of recommendations was rated according to the GRADE system. Three types of biomarkers are discussed: (1) those associated with the risk of rejection (alloreactivity/tolerance), (2) those reflecting individual response to immunosuppressants, and (3) those associated with graft dysfunction. Analytical aspects of biomarker measurement and novel pharmacokinetic–pharmacodynamic models accessible to the transplant community are also addressed. Conventional pharmacokinetic biomarkers may be used in combination with those discussed in this article to achieve better outcomes and improve long-term graft survival. Our group of experts has made recommendations for the most appropriate analysis of a proposed panel of preliminary biomarkers, most of which are currently under clinical evaluation in ongoing multicentre clinical trials. A section of Next Steps was also included, in which the Expert Committee is committed to sharing this knowledge with the Transplant Community in the form of triennial updates.

*Pharmacology and Toxicology Laboratory, Biomedical Diagnostic Center (CDB), Hospital Clinic of Barcelona, University of Barcelona, Spain;

Klinikum Stuttgart, ZentralInstitut für Klinische Chemie und Laboratoriumsmedizin, Stuttgart, Germany;

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

§Department of Nephrology, University of Heidelberg, University Hospital Heidelberg and Mannheim, Heidelberg;

Medizinische Klinik mit Schwerpunkt Nephrologie, Charité Universitätsmedizin Berlin, Germany;

Louvain Centre for Toxicology and Applied Pharmacology, Institut de Recherche Expérimentale et Clinique and Clinical Chemistry Department, Université catholique de Louvain, Cliniques Universitaires Saint-Luc, Brussels, Belgium;

**C42 Clinical Research & Development, Department of Anesthesiology, University of Colorado, Aurora;

††Immunology Laboratory, Hospital Universitario Marqués de Valdecilla-IDIVAL, Santander, Spain;

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

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

¶¶U850 INSERM, Université de Limoges, CHU Limoges, France;

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

***Liver Diseases Department, National Center for Liver Transplantation, Hospital Central de las Fuerzas Armadas, Montevideo, Uruguay;

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

‡‡‡Department of Clinical Pharmacology, University Medical Center Göttingen, Georg-August University, Göttingen, Germany.

Correspondence: Mercè Brunet, PhD, Pharmacology and Toxicology Laboratory, Biomedical Diagnostic Center (CDB), Hospital Clinic of Barcelona, University of Barcelona, Villarroel 170, 08036 Barcelona, Spain (e-mail: mbrunet@clinic.ub.es).

Supported by an unrestricted educational grant awarded to the International Association of Therapeutic Drug Monitoring and Clinical Toxicology by Astellas-Pharma, Novartis-Pharma, and Teva-Pharma.

M. Brunet has received grant support from Novartis Pharma, Astellas Pharma, Teva Europe, and Siemens Healthcare as well as lecture and consulting fees from Astellas and Novartis. M. Shipkova's institution received research funding from Novartis Pharma (Nürnberg, Germany), Roche Diagnostics (Manheim, Germany), and Siemens Healthcare (Eschborn, Germany). T. van Gelder has received grant support from Pfizer and Chiesi as well as lecture and consulting fees from Astellas, Chiesi, Novartis, Teva, and Roche Pharmaceuticals. E. Wieland's institution received research funding from Novartis Pharma (Nürnberg, Germany), Roche Diagnostics (Mannheim, Germany), and Siemens Healthcare (Eschborn, Germany). C. Sommerer received speaker's fee and travel expenses from Novartis Pharma GmbH. The institution received research grants from Novartis Pharma, Astellas Pharma, and Fresenius. K. Budde has consultancy agreements with Bristol-Myers Squibb, Hexal, Veloxis, Chiesi, Novartis Pharma, and Pfizer; and has received research grants for clinical studies, speaker's fees, honoraria, travel expenses, and payment for development of educational presentations from AiCuris, Astellas, Bristol-Myers Squibb, Hexal, Veloxis, Chiesi, Novartis Pharma, Roche AG, Siemens, Fresenius, and Pfizer. U. Christians has received research funding from Novartis Pharmaceuticals Corp. (Easy Hanover, NJ) and Novartis Pharma AG (Basel, Switzerland). M. J. Barten received honoraria, consulting fees, and travel support from Novartis Pharma Sanofi-Aventis GmbH, Biotest AG, and HeartWare Inc. P. Marquet has participated in expert boards for Novartis, Astellas, Sandoz, and Chiesi. D. A. Hesselink has received grant support from Bristol-Myers Squibb and Astellas Pharma, as well as lecture and consulting fees from Astellas Pharma, Chiesi Pharmaceuticals, MSD, and Roche Pharmaceuticals. M. Oellerich received research funding and a consultancy fee from Novartis (Nürnberg, Germany); board membership, stock options, and travel expenses from Chronix Biomedical (San Jose). The other authors declare no conflict of interest.

P. Wallemacq and M. Oellerich are senior authors.

Received September 14, 2015

Accepted January 23, 2016

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