Everolimus with Optimized Cyclosporine Dosing in Renal Transplant Recipients: 6-Month Safety and Efficacy Results of Two Randomized Studies

Abstract

Two prospective, randomized studies evaluated everolimus 1.5 vs. 3 mg/day with steroids and lowexposure cyclosporine (CsA) (C 2 monitoring) in de novo renal transplant patients. Everolimus dosing was adjusted to maintain a minimum trough level of 3 ng/mL. Study 1 (A2306; n = = 237) had no induction therapy; in Study 2 (A2307; n = = 256) basiliximab was administered (Days 0 and 4). The primary endpoint was renal function at 6 months. CsA C 2 target levels, initially 1200 ng/mL in Study 1 and 600 ng/mL in Study 2, were tapered over time post-transplant. Median creatinine levels in Study 1 were 133 and 132 lmol/L at 6 months in the 1.5 and 3 mg/day groups, respectively, and 130 lmol/L in both groups in Study 2. Biopsyproven acute rejection (BPAR) occurred in 25.0% and 15.2% of patients in the 1.5 and 3 mg/day groups in Study 1, and 13.7% and 15.1% in Study 2. Incidence of BPAR was significantly higher in patients with an everolimus trough < < 3 ng/mL. There were no significant between-group differences in the composite endpoint of BPAR, graft loss or death, nor any significant between-group differences in adverse events in either study. Concentration-controlled everolimus with lowexposure CsA provided effective protection against rejection with good renal function.

Association of Clinical Events With Everolimus Exposure in Kidney Transplant Patients Receiving Low Doses of Tacrolimus

“…Kidney transplant patients receiving immunosuppressive therapy with mTOR inhibitors can benefit from less nephrotoxicity by reducing their exposure to CNIs 3, 4, 5, 6, 7, 8. There is a paucity of published data on the use of EVR in combination with Tac in de novo renal transplant recipients.…”

Long-term outcome of everolimus treatment in transplant patients

“…Trials in renal transplantation included a Phase II study evaluating everolimus in combination with either full-dose or reduced-dose cyclosporine and corticosteroids (Study 156), 23 two Phase III trials comparing everolimus vs mycophenolate mofetil when combined with full-dose cyclosporine and corticosteroids (Study 201 and Study 251), [24][25][26] and two trials evaluating concentration-controlled everolimus in combination with reduced-dose cyclosporine and corticosteroids (Study 2306 and Study 2307). 27 More recently, trials in renal transplantation attempting to minimize or withdrawal cyclosporine have been successfully performed.…”

“…In these prospective, randomized studies (A2306 and A2307), the primary endpoint was renal function at 6 months, and the secondary endpoints included incidence of efficacy failure (first occurrence of either biopsy-proven acute rejection, graft loss, death, or loss to follow-up). 27 Everolimus dosing was adjusted to maintain a trough level $3 ng/mL. For the first time in the everolimus studies, the concept of therapeutic dose monitoring was introduced.…”

Activity of everolimus (RAD001) in relapsed and/or refractory multiple myeloma: a phase I study

“…[19][20][21][22] The rapalogue everolimus (RAD001) is approved for immunosuppression and for the treatment of several malignancies such as metastatic renal cell cancer, gastroenteropancreatic neuroendocrine tumor and subependymal giant cell astrocytoma. [23][24][25][26][27][28][29][30] In this investigator-initiated phase I study the safety and activity of everolimus in relapsed or refractory MM were evaluated.…”