Journal
EXPERT OPINION ON INVESTIGATIONAL DRUGS
Volume 11, Issue 12, Pages 1845-1857Publisher
TAYLOR & FRANCIS LTD
DOI: 10.1517/13543784.11.12.1845
Keywords
acute rejection; Certican (TM); chronic rejection; cyclosporine; cyclosporine-sparing; cytomegalovirus; everolimus; mycophenolate mofetil; transplantation; vascular remodefling
Categories
Ask authors/readers for more resources
Everolimus (Certican((TM))) is being developed for prevention of acute and chronic rejection of solid organ transplants. A novel proliferation inhibitor, everolimus synergies with cyclosporine to prevent and reverse acute rejection in preclinical models of kidney, heart or lung transplantation. The manifestations of chronic rejection that may contribute to graft loss are also inhibited by everolimus in preclinical models. Although everolimus is metabolised by the cytochrome P450 CYP3A isoenzyme, coadministration with cyclosporine does not alter the pharmacokinetics of cyclosporine, but cyclosporine coadministration increases exposure to everolimus. Everolimus interacts with inhibitors and inducers of this system; its clearance is reduced in patients with hepatic impairment. In an immunosuppressive regimen with cyclosporine microemulsion formulation and corticosteroids, transplant recipients treated with everolimus show low rates of acute rejection and, in one heart and one renal trial, lower rates of cytomegalovirus infection. Acute rejection rates are lower than those seen with azathioprine in cardiac transplant recipients and similar to those seen with mycophenolate mofetil in renal transplant recipients. Low rates of acute rejection are maintained when everolimus is given as part of a quadruple immunosuppressive regimen with low-dose cyclosporine in renal transplant recipients, with the added benefit of better renal function compared with full-dose cyclosporine. Use of C-2 monitoring to optimise cyclosporine exposure and enhance efficacy and safety of everolimus is planned in future studies. Hypertriglyceridaemia and hypercholesterolaemia have been associated with everolimus, but these effects are not close-limiting. There is no clear upper therapeutic limit of everolimus. However, thrombocytopenia occurs at a rate of 17% at everolimus trough serum concentrations above 7.8 ng/ml in renal transplant recipients. There are limited safety data available in patients with trough concentrations > 12 ng/ml. Studies suggest everolimus targets primary causes of chronic rejection by reducing acute rejection, allowing for cyclosporine dose reduction (which may lead to improved renal function relative to full-dose cyclosporine) and by reducing cytomegalovirus infection and inhibiting vascular remodelling.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available