Bd. Kahan et al., POTENTIAL APPLICATIONS OF THERAPEUTIC DRUG-MONITORING OF SIROLIMUS IMMUNOSUPPRESSION IN CLINICAL RENAL-TRANSPLANTATION, Therapeutic drug monitoring, 17(6), 1995, pp. 672-675
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.