Everolimus

General information

Everolimus is an immunosuppressive macrolide that also has synergistic actions with ciclosporin and interrupts the proliferative responses of vascular and bronchial smooth muscle cells. In a phase I trial, its safety profile and pharmacokinetics were assessed during a 4-week course of once-daily sequential ascending doses (0.75, 2.5, or 7.5 mg/day) in renal transplant recipients on a stable regimen of ciclosporin and prednisone [ ]. Pharmacokinetic data showed dose proportionality, a good correlation between trough and AUC concentrations, and moderate accumulation (2.5-fold). Absorption was within 2 hours, and the half-life was 16–19 hours. There was no evidence of a pharmacokinetic interaction of ciclosporin with everolimus. Virtually every patient in this study had at least one adverse event and 43% of patients treated with everolimus 7.5 mg/day had serious adverse events. In all everolimus groups there was an increased incidence of infectious episodes ( Herpes simplex , upper respiratory infections, pharyngitis, pneumonia, and sinusitis). Similarly, adverse events involving the gastrointestinal system (diarrhea, nausea, and vomiting) were more common. Serum concentrations of triglycerides and total cholesterol increased significantly over time. Individuals treated with everolimus 7.5 mg/day had significant falls in white cell count (– 2.6%) and platelet count (– 51%); the nadir occurred on day 19 and the cell counts recovered spontaneously without withdrawal of the drug. Serum creatinine concentrations and blood pressure did not change. Adverse reactions such as paronychia have also been reported in patients taking everolimus [ ].