REVIEW ARTICLE Biomarkers as a Tool for Management of Immunosuppression in Transplant Patients Eberhard Wieland, MD,* Christoph J. Olbricht, MD,† Caner Su¨sal, MD,‡ Purevtseren Gurragchaa,§ k Torsten Bo¨hler, PhD,¶ Moshe Israeli, MSc,** Claudia Sommerer, MD,†† Klemens Budde, MD, k Bertram Hartmann, MD,‡‡ Maria Shipkova, MD,* and Michael Oellerich, MD§§ Abstract: Therapeutic drug monitoring is a well-established ap- proach in transplantation medicine to guide immunosuppressive therapy. However, it cannot always predict the effects of immuno- suppressive drugs on immune cells, because it does not reflect any aspect of an individual patient’s immune system. Pharmacodynamic monitoring is a more recent strategy to provide information about the biologic effect of a specific drug or drug combination on the in- dividual transplant patient. Currently, there is a large number of different biomarkers that either directly (specific markers) or in- directly (global markers) relate to the pharmacodynamic effects of immunosuppressive drugs and are under investigation as potential candidates to be introduced in clinical practice. Such biomarkers may be useful to identify patients at risk of developing acute rejection, infection, or cancer as well as patients who are suitable for mini- mization of immunosuppressant therapy and may be helpful to manage the timing and rate of immunosuppressant weaning. Serial longitudinal monitoring may allow maintenance of an individualized immunosuppressive regimen. Thus, biomarker monitoring is a potential complementary tool to therapeutic drug monitoring. This review summarizes the current state of knowledge about the use of a number of global or drug-specific pharmacodynamic biomarkers. It is not a comprehensive overview of the literature available, but rather an evidence-based reflection by experts who are intensively involved in scientific work in this field. Key Words: immunosuppression, biomarkers, transplantation, therapeutic drug monitoring, pharmacodynamics (Ther Drug Monit 2010;32:560–572) INTRODUCTION The therapeutic window of immunosuppressive (IS) drugs used in transplantation medicine is critically narrow. Empiric dosing can result in side effects such as infection, cancer, and cardiovascular diseases or in underimmunosup- pression associated with graft rejection and graft loss. The pharmacodynamic (PD) effects of numerous drugs correlate better with their blood or plasma concentrations rather than with the administered dose, which is the rationale of therapeutic drug monitoring (TDM). However, it has also been shown that drugs can have different effects in different patients although drug concentrations and dosages are the same. The relationship between pharmacokinetics (PK) and pharmacodynamics is therefore of particular interest. 1 Inter- subject variability in the sensitivity to suppression of immune function may occur and therefore the assessment of immunologic risks before transplantation could be useful. Furthermore, the application of multiple IS drugs may exert additive, synergistic, or antagonistic pharmacologic effects, emphasizing the limitation of only PK monitoring. 2 Measuring biomarkers in addition to drug concentrations may be useful to predict PD effects in an individual patient. These biomarkers can be the primary drug targets (eg, IMPDH for mycophenolic acid) or secondary modulated mediators. However, whereas the TDM approach is already well established in routine laboratory assessments, pharmacogenetics and PD monitoring are currently used predominantly as experiments in clinical trials. This review summarizes the current state of knowledge about the use of a number of global or drug-specific PD- related biomarkers that are under investigation and seem to be promising candidates to be included in the management of immunosuppression. It is not a comprehensive overview of the literature available, but rather an evidence-based reflection by experts who are intensively involved in scientific work in this field. Received for publication April 5, 2010; accepted June 29, 2010. From the *Zentralinstitut fu¨r Klinische Chemie und Laboratoriumsmedizin, Klinikum Stuttgart, Stuttgart, Germany; †Klinik fu¨r Nieren- und Hochdruckkrankheiten und Transplantationszentrum, Klinikum Stuttgart, Stuttgart, Germany; ‡Abteilung Transplantationsimmunologie, Institut fu¨r Immunologie, Ruprecht-Karls-Universita¨t, Heidelberg, Germany; §As- klepios Klinikum Uckermark, Klinik fu¨r Urologie, Schwedt/Oder, Germany; k Abteilung Nephrologie, Charite´ Universita¨tsmedizin, Humboldt-Universita¨t, Berlin, Germany; {Gambro Dialysatoren GmbH, R&D, Hechingen, Germany; **CAIR Institute, Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel; ††Universita¨tsklinikum Heidelberg, Medizinische Klinik und Poliklinik, Sektion Nephrologie, Ruprecht-Karls Universita¨t, Heidelberg, Germany; ‡‡Zentrum fu¨r Innere Medizin, Sektion Nephrologie, Universita¨t Ulm, Ulm, Germany; and §§Zentrum Innere Medizin, Abteilung Klinische Chemie, Universita¨ts- medizin Go¨ttingen, Georg-August Universita¨t, Go¨ttingen, Germany. The authors disclose funding received for this work from any of the following organizations: National Institutes of Health; Welcome Trust; Howard Hughes Medical Institute; and others. Correspondence: Maria Shipkova, MD, Zentralinstitut fu¨r Klinische Chemie und Laboratoriumsmedizin, Klinikum Stuttgart, Kriegsbergstr.60, D-70174 Stuttgart, Germany (e-mail: m.shipkova@klinikum-stuttgart.de). Copyright Ó 2010 by Lippincott Williams & Wilkins 560 Ther Drug Monit  Volume 32, Number 5, October 2010