Drug Monitoring of Sirolimus and Everolimus/Drug-Monitoring von Sirolimus und Everolimus

Abstract

Sirolimus (Rapamune â ) and everolimus (Certican TM ) are macrocyclic lactones with a novel mechanism of immunosuppressive action that act in synergy with the calcineurin inhibitors cyclosporine and tacrolimus. Both sirolimus and everolimus are rapidly absorbed (t max 1±2 h), but they have a relatively low systemic bioavailability. Sirolimus has a prolonged half-life (ca. 60 h) and is therefore administered once daily, whereas everolimus has a shorter half-life (ca. 17.5 h) and is normally given twice daily. Both drugs show substantial inter-and intraindividual variation in their pharmacokinetics. They are metabolized by the cytochrome P-450 3A (CYP3A) system and they are also substrates for P-glycoprotein. Drug-drug interactions are therefore observed with inhibitors or inducers of CYP3A/P-glycoprotein. The major side effects associated with sirolimus and everolimus appear to be hypercholesterolaemia, hypertriglyceridaemia, thrombocytopenia and leucopenia. However, in contrast to the calcineurin inhibitors, they are not nephrotoxic. Several analytical procedures based on HPLC-UV, liquid chromatography-mass spectrometry (LC-MS), or liquid chromatography-tandem mass spectrometry (LC-MS/ MS) have been described for the quantification of sirolimus. In the case of everolimus, LC-MS and LC-MS/MS methods have been reported. As yet, immunoassays are not available. A provisional therapeutic range for trough whole-blood sirolimus concentrations, measured using a chromatographic procedure, in renal transplant recipients receiving cyclosporine and corticosteroids as concomitant immunosuppression is 4±12 mg/L. If cyclosporine therapy is discontinued, a target trough range of 12±20 mg/L is recommended. A therapeutic range for everolimus has not yet been established. A significantly increased risk of acute rejection has been documented at everolimus trough levels below 3 mg/L when used in combination with cyclosporine and steroids. Zusammenfassung: Sirolimus (Rapamune â ) und Everolimus (Certican TM ) sind cyclische Makrolide mit einer a,b-Diketoamid-Bindung. Sie weisen einen anderen Mechanismus der Immunsuppression als die bisher verwendeten Calcineurin-Inhibitoren (Cyclosporine und Tacrolimus) auf, welche jedoch mit einer synergistischen Wirkung in Kombinationstherapie eingesetzt werden ko Ènnen. Sirolimus und Everolimus werden beide schnell adsorbiert (t max 1±2 Std), haben jedoch eine geringe Bioverfu Ègbarkeit. Sirolimus wird aufgrund seiner relativ langen Halbwertszeit (ca. 60 Std) nur einmal ta Èglich gegeben, wa Èhrend Everolimus mit einer ku Èrzeren Halbwertszeit (ca. 17,5 Std) zweimal ta Èglich gegeben wird.