A review on therapeutic drug monitoring of the mTOR class of immunosuppressants: everolimus and sirolimus

Immunosuppression plays a key role in the prevention of organ rejection in transplant recipients and in the treatment of diverse autoimmune disorders. Therapeutic drug monitoring (TDM) for the mammalian target of rapamycin inhibitors (mTOR) class of immunosuppressants is mandatory in the clinical setting because of the narrow therapeutic index, high intersubject pharmacokinetic variability, under- and over-immunosuppression and adverse effects of these drugs. Immunosuppressive drug therapy is frequently individualized based on the organ transplanted, time after transplantation, and transplant centre-specific immunosuppressive protocols. Since predose trough concentrations (C_o) correlate well with areas under the curve, C_o levels are commonly used as predictable indices when monitoring everolimus and sirolimus. In kidney transplantation, the lowest incidence of adverse events is generally detected when everolimus C_o is 3–8 ng/mL in combination therapy with ciclosporin and glucocorticoids. A regimen of mTOR inhibitors + tacrolimus minimization therapy reduced nephrotoxicity better than standard-dose tacrolimus, without significant changes in mortality or biopsy-proven acute rejection. Sirolimus whole blood C_o should be set between 5 and 15 ng/mL, depending on the immunological risk, time of conversion and use of other immunosuppressive drugs. As per the Kidney Disease: Improving Global Outcomes recommendations, because of potential nephrotoxicity, the use of sirolimus and ciclosporin should be avoided during the early course of therapy. The evidence-based recommendations discussed in this review are useful for the optimal implementation of TDM in routine clinical practice. Avoiding calibration bias using whole blood calibrators, and the use of an external proficiency testing programme to improve analytical performance are highly recommended.