PROCEEDINGS PAPER Target Enzyme Activity as a Biomarker for Immunosuppression Petra Glander, PharmD and Klemens Budde, MD Abstract: Pharmacokinetic drug monitoring has been used for many years to relate immunosuppressant dose to drug exposure in vivo. However, this conventional therapeutic drug monitoring of blood immunosuppressant levels may not necessarily predict the pharmacologic effects on immune cells. The direct determination of target enzyme activity (eg, calcineurin activity, inosine-5#-mono- phospahte dehydrogenase [IMPDH] activity, p70S6 kinase) may help to better assess the individual response to the immunosuppressant. However, its use is limited by the difficulties of the assay systems, which did not allow yet the prospective assessment of these enzymes in larger patient cohorts with the establishment of validated phar- macodynamic drug monitoring. The most progress regarding a robust and reproducible test system has been achieved with the de- termination of IMPDH activity as a specific pharmacodynamic pa- rameter of mycophenolic acid activity. This recently validated and standardized assay allows the investigation of IMPDH activity in larger clinical studies. Although the determination of target enzyme activity, eg, by the determination of IMPDH activity, holds promise for a more individualized therapy in transplant medicine, more studies are needed to prospectively validate this approach. Key Words: pharmacodynamics, immunosuppression, IMPDH activity, calcineurin activity, mTOR inhibitors (Ther Drug Monit 2010;32:257–260) INTRODUCTION Modern immunosuppressive therapy in transplantation should provide an efficacious regimen while minimizing toxicities. Currently, the combination of synergistic drugs is the main strategy to prevent early acute rejection and to provide long-term effective rejection prophylaxis. Combina- tions of calcineurin inhibitors (cyclosporine or tacrolimus) and antiproliferative drugs (mycophenolic acid [MPA]) or mTOR inhibitors (sirolimus and everolimus) with or without antibody induction and steroids are used. 1 Clinical research addresses the evaluation of factors, which can further improve the efficacy and tolerability of single immunosuppressive agents or treatment regimens. 2 Pharmacokinetic Approach Over the last years, the importance of therapeutic drug monitoring (TDM) of immunosuppressive drugs has been recognized to improve rejection rates and to limit drug specific toxicities and infections resulting from over immunosuppres- sion. 3 The TDM approach involves the measurement of pharmacologic surrogate markers to adjust drug dosage. The measurement of pharmacokinetic surrogate markers for drug exposure (area under concentration curve) evaluates what the ‘‘body does to the drug,’’ eg, absorption, distribution, metabolism, and excretion of the drug. Ideally, the pharma- cokinetic surrogate marker has an excellent correlation with drug exposure and the immunosuppressant, a well-defined therapeutic window. In clinical practice, evaluation of predose drug concen- trations to guide drug dosing is routinely established for calcineurin inhibitors and mTOR inhibitors. Mycophenolates (either mycophenolate mofetil [MMF] or enteric-coated myco- phenolate sodium) have become standard immunosuppres- sants after solid organ transplantation worldwide. 4,5 The immunosuppressive activity of both mycophenolate formula- tions is based on the reversible inhibition of inosine-5#- monophospahte dehydrogenase (IMPDH) by MPA. 6 The high interpatient variability of MPA pharmacokinetics with in- creasing drug exposure over time and a potential for pharma- cokinetic drug interactions would make TDM for MPA desirable to improve efficacy and to avoid toxicity. 7–11 There is consensus that a lower threshold of MPA exposure of 30 mg*h/L should be achieved within the first months after transplantation in calcineurin inhibitor-based regimens. How- ever, a firm therapeutic window for all MPA-treated patients has not been established yet. 7–11 Pharmacodynamic Approach The conventional TDM of blood immunosuppressant levels may not necessarily predict the pharmacologic effects on immune cells. Any pharmacokinetic monitoring depends on the assumption that a certain drug level will have the same effect in all individuals. Pharmacodynamics is another approach in TDM and directly reflects the drug’s biologic effects. 12,13 The ideal pharmacodynamic parameter should meet several criteria to add further information/improvements to pharmacokinetic-guided therapy. The target of interest is specific for a drug and closely related to the principal mechanism of action. Of special interest are targets that dis- play in vivo a high interindividual variability in the absence of the drug and/or which are gradually modifiable under therapy. An intracellular located target can reflect intracellulary Received for publication March 15, 2010; accepted March 15, 2010. From the Department of Nephrology, Charite´ Universita¨tsmedizin Berlin, Berlin, Germany. Correspondence: Professor Klemens Budde, Universita¨tsklinikum Charite´, Medizinische Klinik mit Schwerpunkt Nephrologie, Schumannstr. 20/21, 10117 Berlin, Germany (e-mail: klemens.budde@charite.de). Copyright Ó 2010 by Lippincott Williams & Wilkins Ther Drug Monit  Volume 32, Number 3, June 2010 257