Abstract

Sirolimus (SRL) (rapamycine) and everolimus (RAD), 40-hydroxy-rapamycine, were recently introduced as proliferation signal inhibitors (PSI) immunosuppressants, acting on the mTOR (target of rapamycine) IL2 synthesis. Due to different development strategies, SRL was registered in renal transplantation with steroids and cyclosporine (CyA) for the first three months, whereas RAD both in renal and cardiac transplantation with steroids and (reduced doses) CyA. Therapeutic drug monitoring (TDM) was recommended to control the enhancement of CyA nephrotoxicity and document RAD therapeutic detectable levels. Target trough concentration range were defined respectively as 3-8 and 4-12 ng/mL for RAD and SRL, the latest increased after CyA withdrawal [12-20]. Dose regimen are 2-5 mg QD (SRL) and 0.75 mg BID (RAD), taking in account the inhibition of CyA on PSI metabolism. Security profile exhibited hyperlipidemia, haematotoxicity, and more specific side effects (interstitial pneumopathy, lymphoceles and mucositis). Pharmacokinetics particularities of these lipophilic drugs resulted in long half-lives, poor bioavailability, intensive metabolism and numerous pharmacokinetic CYP3A4 drug interactions. Interindividual variability appeared more important than intraindividual. PSI exhibited similar pharmacodynamics but RAD appeared easiest to manage in clinical practice, due to its reduced halflife (30 h) as compared to SRL (60 h). TDM is performed using LC-MS/MS, but immunoassays are available from Abbott (MEIA, SRL) and Seradyn (Innofluor FPIA, RAD), exhibiting cross reactions (>80%) with metabolites and between PSI. International proficiency testing schemes are available (www.bioanalytics.uk). The place of these drugs in the immunosuppressive strategy has to be settled in the future, specially regarding delayed graft dysfunction prevention.

Keywords: Sirolimus, Everolimus, immunosuppressants