Everolimus

Everolimus (also known as SZD RAD) is a structural analogue of sirolimus with an additional hydroxyethyl group (Fig. 3). Everolimus is currently in phase III clinical trials in the USA and has not received FDA approval for use as an immunosuppressive agent. Because everolimus is still in the experimental stage it will only be briefly discussed.

4.2.1. Pharmacokinetics

Everolimus has improved bioavailability (161,162) and a shorter elimination half-life (~24h) than sirolimus (163). Everolimus also has lower intrapatient drug variability than sirolimus (144,164). Concomitant use of CsA results in increased everolimus blood concentrations due to inhibition of everolimus metabolism (165). Similar to sirolimus, everolimus is metabolized in the intestine and liver by cytochrome P450 enzymes. At least 20 metabolites have been identified (166), with mono-hydroxyl, di-hydroxyl, demethylated, and an open ring form being the major metabolites (167). Metabolites are in relatively low concentrations when monitoring trough blood concentrations (167).

4.2.2. Methods of Analysis

Immunoassays to measure everolimus are not currently available in the USA and most likely will lag behind FDA approval of the drug. Seradyn has developed an FPIA (Innofluor Certican Assay System) to measure whole blood everolimus outside the USA on Abbott TDx instrumentation (168). The FPIA method has a functional sensitivity of 2 ^g/L (168), which is just below the therapeutic trough blood concentration lower limit of 3 ^g/L (169). When compared with HPLC-MS, the FPIA has a positive mean bias of 24.4% in renal transplant recipients (170). The positive bias is due to differences in calibrator-assigned values and antibody cross-reactivity with everolimus metabolites (170). Cross-reactivity with metabolites ranges from 5 to 72% (168). HPLC-UV and HPLC-MS methods are also available to measure everolimus (171,172).

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