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

Sirolimus is a potent immunosuppressive agent with a novel mechanism o f action. It inhibits the transduction of cytokine signals necessary f or the proliferation and maturation of T cells. Because sirolimus bloc ks 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 a mong human renal allograft recipients. However, Phase I studies docume nt 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 l evel to AUC. Development of a monoclonal antibody assay system may sim plify the monitoring of drug concentrations further. Additional studie s of sirolimus will be required to determine the therapeutic concentra tions and ratios of sirolimus to CsA that provide optimal immunosuppre ssion, and to assess the possibility of a steroid-free regimen.