Everolimus

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Abstract
Everolimus (Certican®) is an orally administered mammalian target of rapamycin inhibitor (proliferation signal inhibitor) derived from sirolimus (rapamycin), which is used as part of immunosuppressant therapy in kidney and heart transplantation. When evaluated as part of triple therapy with ciclosporin and corticosteroids, everolimus showed equivalent efficacy to mycophenolate mofetil after renal transplantation, and superiority to azathioprine in cardiac transplant recipients, in terms of reducing efficacy failure after transplantation. Everolimus potentiates ciclosporin-associated nephrotoxicity, and it is recommended that concentration-controlled everolimus is used with reduced-dosage ciclosporin in order to limit renal toxicity while retaining immunosuppressive efficacy. Ongoing trials with everolimus, such as the evaluation of ciclosporin-withdrawal strategies, should help clarify its optimal usage. The use of everolimus may be associated with reduced rates of cytomegalovirus (CMV) infection and of cardiac allograft vasculopathy. Available data suggest that everolimus may be cost-neutral for healthcare providers. Everolimus inhibits growth factor-stimulated cell proliferation of haematopoietic and nonhaematopoietic cells through the formation of a complex with FK506 (tacrolimus)-binding protein 12 (FKBP12). This complex binds to FKB12-rapamycin-associated protein, blocking its activity, which includes the phosphorylation of p70 S6 kinase, and subsequent protein synthesis. Exposure-response data show a link between trough blood concentrations of everolimus and risk of acute allograft rejection in renal transplant patients, and the drug has been shown to inhibit vascular remodelling in preclinical studies and fibroblast proliferation in tissue from lung transplant patients. Synergism of everolimus with other agents, including ciclosporin, fingolimod and mycophenolate mofetil, has been noted in preclinical studies. There is no evidence of antagonism between everolimus and tacrolimus in terms of lymphocyte proliferation. Everolimus displays dose-proportional pharmacokinetics, with rapid absorption leading to peak blood concentrations being attained within 1–2 hours of an oral dose. Steady state is generally achieved by day 4. More than 75% of the drug is sequestered into red blood cells; 75% of the fraction in plasma is bound to plasma proteins. Metabolism is chiefly via hepatic cytochrome P450 (CYP) enzymes 3A4, 3A5 and 2C8, and approximately 98% is excreted in bile as metabolites. Bioavailability is affected markedly by the presence of food, and apparent clearance is reduced in patients with moderate hepatic impairment. The elimination half-life of everolimus is 24–35 hours. Everolimus and ciclosporin are both metabolised by the CYP3A isoenzyme system, and their concomitant administration increases everolimus exposure by 2- to 3-fold. Drugs that are likely to affect the clearance of everolimus through induction or inhibition of CYP3A enzymes include erythromycin, azithromycin, ketoconazole, itraconozole and rifampicin. Oral everolimus 1.5 or 3 mg/day, in combination with full-dosage ciclosporin microemulsion and corticosteroids, has been shown to be as effective as mycophenolate mofetil 2 g/day in the prevention of efficacy failure after kidney transplantation in two major randomised, international trials in a total of 1171 patients. Both trials ran for 3 years and were double-blind in the first year. The primary endpoint, ‘efficacy failure’ at 6 or 36 months, was a composite of biopsy-proven acute rejection (BPAR), graft loss, death or loss to follow-up. In one trial, graft survival was significantly better in the everolimus 1.5 mg/day group than in the 3 mg/day group after 36 months. Rates of mortality were similar across all groups, with >90% of patients surviving to 36 months in both studies. Full dosages of ciclosporin were used initially in both trials, although a subsequent protocol amendment reduced ciclosporin exposure because of concerns over increases in circulating creatinine levels in the everolimus-plusciclosporin groups, which suggested that everolimus potentiated ciclosporin-associated nephrotoxicity. After the introduction of the amendment, renal function stabilised in the everolimus groups, but serum creatinine values remained higher in these groups than among mycophenolate mofetil recipients. The same dosages of everolimus, adjusted to ensure everolimus trough blood concentrations (Cmin) of ≥3 ng/mL, were given with reduced dosages of ciclosporin in two open-label studies in a total of 493 patients. Induction therapy with basiliximab was also used in one of these trials. Rates of efficacy failure over 24 months were similar between groups overall, and BPAR was less common in patients treated with everolimus plus reduced-dosage ciclosporin who maintained a mean Cmin of everolimus in blood of ≥3 ng/mL. Everolimus 1.5 or 3 mg/day was compared with azathioprine 1–3 mg/kg/day (both combined with full-dosage ciclosporin) in a large, randomised trial in 634 adults undergoing primary heart transplantation, with follow-up data available for 4 years. Efficacy failure was a composite of the incidence of BPAR (International Society for Heart and Lung Transplantation grade 3A or greater), rejection associated with haemodynamic compromise, graft loss or retransplantation, and death or loss to follow-up. Both dosages of everolimus were significantly more effective than azathioprine in preventing efficacy failure over 4 years of follow-up. Patient survival rates were similar across all treatment groups. Both dosages of everolimus were also significantly more effective than azathioprine at reducing the incidence of cardiac allograft vasculopathy as indicated by intravascular ultrasound. There was evidence of an association between increasing everolimus exposure and reduced severity of vasculopathy after 12 months. Looking at...