2 Clinical pharmacokinetics and pharmacodynamics of mTOR inhibitors in renal transplantation

The mammalian target of rapamycin (mTOR) inhibitors sirolimus and everolimus are a relatively new therapeutic group in renal transplantation and have shown their efficacy in recent trials. Their main advantage compared to the calcineurin inhibitors cyclosporine and tacrolimus are their relative lack of nephrotoxicity. Sirolimus differs from everolimus mainly in pharmacokinetic characteristics such as elimination half-life and bioavailability. The oral mTOR inhibitors exert both highly variable interand intraindividual pharmacokinetics. They are metabolized by CYP3A4, CYP3A5 and CYP2C8 enzymes and are substrates for P-glycoprotein and share similar pharmacodynamics. Polymorphisms in genes coding for these enzymes might be of interest for optimizing immunosuppressive therapy. The most important side effects of sirolimus and everolimus are thrombocytopenia, leukopenia, hypercholesterolemia, diarrhea and although rare but potentially life threatening interstitial pneumonia. The narrow therapeutic window of mTOR inhibitors, together with high variability in pharmacokinetics, makes therapeutic drug monitoring essential for individualizing the dose and thereby preventing toxicity or rejection. The main future challenge is to further optimize mTOR inhibitor based immunosuppressive therapy. 17 Clinical pharmacokinetics and pharmacodynamics of mTOR inhibitors in renal transplantation 2 Introduction In the last 30 years considerable progress has been made in the field of renal transplantation with regard to immunosuppression, since the calcineurin inhibitors (CNIs) cyclosporine and later on tacrolimus came available to the clinic. However, despite this success, calcineurin inhibitors are also associated with severe toxicity such as acute and chronic nephrotoxicity [1,2]. In an effort to find new immunosuppressive drugs without or less nephrotoxicity mTOR inhibitors were introduced in renal transplantation. The mTOR inhibitors sirolimus (Rapamune®) and everolimus (Certican®) are potent orally administered immunosuppressive agents. Both are derived from a macrocyclic lactone produced by streptomyces hygroscopicus recovered from Easter Island [3,4]. Similarities exist between other macrocyclic lactones such as erythromycin and tacrolimus with regard to their chemical structures. Although highly active against Candida Albicans sirolimus was commercially launched for its immunosuppressive potency discovered in animals [5,6] and later suggested for clinical renal transplantation [7]. Everolimus is a derivative of rapamycin (sirolimus) and was developed for prevention of acute and chronic rejection of solid organ transplants. Instead of a hydrogen atom at position 40 it has a 2-hydroxethyl chain (Figure 1a en 1b) substitution which improves the solubility and bioavailability of the drug [4]. Figure 1: Chemical structure of Sirolimus and Everolimus. In the past years mTOR inhibitors were only prescribed in combination with cyclosporine and steroids since a synergistic effect and different mechanism of action is present compared to CNIs [8,9], but as a result of the damaging effects of cyclosporine on the donor kidney everolimus is now tested in absence of cyclosporine in clinical trials [10,11]. a b