Introduction

In recent years, improved knowledge of the immunological mechanisms underlying transplant rejection, as well as the discovery of novel biological and pharmaceutical agents, which selectively block various steps of the immune response, has enabled the effective control of graft rejection by the use of combined immunosuppressive therapy. Because of their complex and variable pharmacokinetics, as well as their narrow therapeutic indices, therapeutic drug monitoring (TDM) is an essential part of patient care, in order to reduce the risks of toxicity or rejection. Most transplant centres using cyclosporin or tacrolimus as primary immunosuppressants for the prophylaxis of graft function rely on trough concentration measurements of these drugs to help guide dosage. Despite its widespread use, this approach has its limitations in that the apparent concentrations of the drug may not accurately reflect the concentrations of the pharmacologically active moieties or may not correlate with the actual concentrations at the site of action of the drug. An alternative approach is pharmacodynamic monitoring in which the biological effect of the drug of interest is determined to assess the state of immunosuppression [1]. This chapter will present a critical appraisal of recent advances in the development of pharmacodynamic markers for the immunosuppressive drugs cyclosporin, tacrolimus, sirolimus, azathioprine and mycophenolate mofetil.

Calcineurin inhibitors (cyclosporin, tacrolimus)

Although structurally quite different, cyclosporin and tacrolimus inhibit the same early events in T-lymphocyte activation, thus preventing T-helper cells from progressing from the G0 to the G1 phase of the cell cycle.