Requirements for therapeutic drug monitoring of sirolimus, an immunosuppressive agent used in renal transplantation

Background: On September 15, 1999, sirolimus received approval from the US Food and Drug Administration (FDA) for marketing as an immunosuppressive agent. As with any chronically administered medication, the question arises whether therapeutic drug monitoring (TDM) is required for optimal therapy. In the case of sirolimus, there are data to suggest that TDM may be beneficial in some patients. Objective: To assess the need for monitoring sirolimus concentrations, this paper reviews the following factors influencing the usefulness of TDM: wide pharmacokinetic variability; toxicity; suspected noncompliance; suspected drug interactions; and specific demographic characteristics. Data supporting the correlation between sirolimus concentration and immunosuppressive efficacy are also discussed. Results: The available literature on sirolimus suggests that TDM may be required in some cases. Studies have shown that there is wide interindividual variability in the pharmacokinetic behavior of drugs in transplant patients; that there is a relationship between blood concentrations of sirolimus and adverse events; and that coadministration of cyclosporine alters the pharmacokinetics of sirolimus. Additionally, the correlation between sirolimus concentration and immunosuppressive efficacy in phase III trials suggests a benefit in transplant patients when sirolimus concentrations reach appropriate levels, Finally, noncompliance is a common occurrence in the transplant population, and monitoring is often necessary in suspected noncompliers. Conclusion: Although additional clinical studies are needed, it appears that TDM is an important aspect of treatment with sirolimus.