[Clinical pharmacokinetics and therapeutic monitoring of tacrolimus]

Abstract

Tacrolimus (FK 506) is a new macrocyclic lactone immunosuppressant which possesses similar but more potent immunosuppressive properties compared with cyclosporin. It is able to inhibit T cell proliferation and the production of interleukine 2 (and other growth promoting cytokines). A major interest of tacrolimus is that it can be used as a rescue therapy since clinical trials have demonstrated its ability to be effective in some patients who develop rejection episodes refractory to current regimens, including corticosteroids. Tacrolimus is highly bound to erythrocytes and is largely metabolized, primarily in the liver, by Cyt P450 3A4. Its excretion pathway concerns the bile almost exclusively. Like cyclosporin, the drug is associated with a range of adverse effects including nephrotoxicity, neurotoxicity and diabetes. Tacrolimus also exhibits a large inter- and intra-individual variability of its pharmacokinetics. Because of this variability and the narrow therapeutic index of tacrolimus, monitoring of tacrolimus blood concentrations would be useful for optimization of therapy. However, even if we know that by maintaining the residual blood concentration under 15 micrograms/l it is possible to reduce dramatically the occurrence of adverse effects, we still have not determined the threshold value of clinical efficacy. This will be important for current and future clinical pharmacology investigations with tacrolimus.