POTENTIAL APPLICATIONS OF THERAPEUTIC DRUG-MONITORING OF SIROLIMUS IMMUNOSUPPRESSION IN CLINICAL RENAL-TRANSPLANTATION

Sirolimus is a potent immunosuppressive agent with a novel mechanism of action. It inhibits the transduction of cytokine signals necessary for the proliferation and maturation of T cells. Because sirolimus blocks a broad spectrum of cytokine signals, it seems logical to use it as an adjunct to CsA-based immunosuppression. The high degree of synergy between these two agents, as suggested by the rigorous median-effect analysis, has been confirmed by a reduced rate of rejection episodes among human renal allograft recipients. However, Phase I studies document wide interindividual variation in the pharmacokinetic parameters of 26 stable renal transplant patients, thereby suggesting that optimal therapy may require monitoring of drug concentrations, which is a task that has been somewhat simplified by the good correlation of trough level to AUC. Development of a monoclonal antibody assay system may simplify the monitoring of drug concentrations further. Additional studies of sirolimus will be required to determine the therapeutic concentrations and ratios of sirolimus to CsA that provide optimal immunosuppression, and to assess the possibility of a steroid-free regimen.