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

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Abstract

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.

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Authors and Affiliations

  1. Department of Pharmaceutics, College of Pharmacy, Gulf Medical University, Ajman, United Arab Emirates

    Shery Jacob

  2. Department of Pharmaceutical Sciences, College of Clinical Pharmacy, King Faisal University, Al-Ahsa, Saudi Arabia

    Anroop B. Nair

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  1. Shery Jacob
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Correspondence to Shery Jacob.

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Shery Jacob and Anroop Nair have no conflicts of interest that are directly related to the content of this work.

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Jacob, S., Nair, A.B. A review on therapeutic drug monitoring of the mTOR class of immunosuppressants: everolimus and sirolimus. Drugs Ther Perspect 33, 290–301 (2017). https://doi.org/10.1007/s40267-017-0403-0

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