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TBase - an Integrated Electronic Health Record and Research Database for Kidney Transplant Recipients
Published on: April 13, 2021
Sirolimus and everolimus in kidney transplantation
Dirk Jan A R Moes1, Henk-Jan Guchelaar1, Johan W de Fijter2
1Department of Clinical Pharmacy & Toxicology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands.
Abstract:
The mammalian target of rapamycin (mTOR) inhibitors sirolimus and everolimus have shown their efficacy in kidney transplantation, but their wider introduction has been limited by relative high discontinuation rates. Their main advantage compared with calcineurin inhibitors (CNIs) is their relative lack of nephrotoxicity. They differ mainly in pharmacokinetic characteristics and have variable inter- and intra-individual pharmacokinetics. They are metabolized by cytochrome (CYP)-3A4/5 and CYP2C8 enzymes and are substrates for P-glycoprotein (P-gp). Their most important adverse effects are thrombocytopenia, leukopenia, hypercholesterolemia, stomatitis, diarrhea, and, although rare, interstitial pneumonitis. The narrow therapeutic window makes therapeutic drug monitoring (TDM) essential to prevent toxicity or rejection. As we discuss here, the main future challenge is to further optimize mTOR inhibitor (mTORi)-based immunosuppressive therapy.
Insights
Mammalian target of rapamycin (mTOR) inhibitors show promise in kidney transplants due to lower nephrotoxicity than calcineurin inhibitors (CNIs). Optimizing their use requires managing side effects and implementing therapeutic drug monitoring (TDM).
Area of Science:
- Pharmacology
- Immunosuppression
- Nephrology
Background:
- Mammalian target of rapamycin (mTOR) inhibitors, sirolimus and everolimus, are effective in kidney transplantation.
- Their use is limited by high discontinuation rates, despite a lower risk of nephrotoxicity compared to calcineurin inhibitors (CNIs).
Purpose of the Study:
- To review the efficacy and challenges of mTOR inhibitors in kidney transplantation.
- To highlight the importance of therapeutic drug monitoring (TDM) for optimizing mTOR inhibitor therapy.
Main Methods:
- Review of existing literature on mTOR inhibitors in kidney transplantation.
- Analysis of pharmacokinetic properties, adverse effects, and drug interactions.
Main Results:
- mTOR inhibitors offer an alternative to CNIs with reduced nephrotoxicity.
- Variable pharmacokinetics and significant adverse effects (thrombocytopenia, leukopenia, hypercholesterolemia) necessitate careful management.
- Therapeutic drug monitoring (TDM) is crucial for maintaining efficacy and minimizing toxicity.
Conclusions:
- Optimizing mTOR inhibitor (mTORi)-based immunosuppressive therapy is a key future challenge in kidney transplantation.
- Further research is needed to refine dosing strategies and manage adverse events for wider clinical adoption.
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