Sirolimus

 

Rapamune TM (Sirolimus) is an immunosuppressive drug marketed by Wyeth Laboratories (now part of Pfizer Inc) and licensed for use in renal transplantation. The following information is extracted from a product monograph.

 

1. INTRODUCTION

Advances in immunosuppressive therapies over the past two decades have improved one­year graft survival, with decreases in the rates of renal allograft acute rejection. Current opinion is that one­year graft survival of around 90% is achievable, but subsequent graft loss of approximately 5% a year remains an intractable problem.1

Several key factors known to reduce long­term graft or patient survival are associated with current immunosuppressive agents. These include chronic renal allograft dysfunction, of which nephrotoxicity is a major contributing factor, and risk factors for cardiovascular disease, specifically hypertension, hyperlipidemia, and post­transplant diabetes mellitus. In addition, current immunosuppressive therapies are associated with neurotoxicity, gastrointestinal side effects, and cosmetic changes, such as gingival hyperplasia, obesity, and hypertrichosis.

RAPAMUNE® (sirolimus) is a new and effective immunosuppressive agent. Isolated from Streptomyces hygroscopicus, RAPAMUNE is a macrocyclic lactone. It has a novel mode of action which does not involve inhibition of calcineurin.2,3 Interest in RAPAMUNE as an immunosuppressant in renal transplantation results, in part, from its novel mechanism of action and its distinct side­effect profile. 3

A key action of RAPAMUNE is to interrupt T­cell cycle transition from G 1 to S phase by inhibiting interleukin­2 signal transduction pathways. Binding of RAPAMUNE to mTOR (mammalian target of rapamycin) inhibits T­cell proliferation by selectively blocking the activation of processes within the cell that are necessary for G 1 to S phase transition. 3,4 Early phase II clinical trials directly compared the effects of RAPAMUNE and cyclosporine on renal function. 2,5 These studies demonstrated that renal transplant patients receiving the RAPAMUNE maintenance regimen benefited from excellent graft survival and showed improved renal function compared to patients receiving cyclosporine­ containing regimens. 2,5 The landmark RAPAMUNE Maintenance Regimen study evaluated whether cyclosporine could be eliminated from a RAPAMUNE/cyclosporine/corticosteroid regimen in the early post­transplant period. This study supported the results of earlier studies in demonstrating effective immunosuppression when RAPAMUNE was used as maintenance therapy, without the nephrotoxic side effects of cyclosporine. 6 In addition, significantly lower blood pressure was reported in patients from whom cyclosporine was withdrawn. 6

RAPAMUNE has been demonstrated to be effective when used in a regimen with cyclosporine elimination. In clinical trials, higher serum creatinine levels and lower glomerular filtration rates were seen in patients treated with RAPAMUNE, cyclosporine, and corticosteroids compared to cyclosporine, corticosteroids, and either azathioprine­ or placebo­treated controls. In contrast, a regimen with RAPAMUNE as base therapy, which eliminates cyclosporine by the end of month 3, results in significant improvement in graft function and a reduction in systolic and diastolic blood pressures. RAPAMUNE may be continued as maintenance therapy with corticosteroids only if cyclosporine can be progressively discontinued.

In summary, RAPAMUNE is the first approved immunosuppressant that allows the withdrawal of a calcineurin inhibitor during maintenance therapy in renal allograft patients.

References:

1. Brenchley PEC, Short CD, Roberts ISD. Is persistent TGF 1 expression the mechanism responsible for chronic renal allograft loss? Nephrol Dial Transplant 1998; 13: 548--551.

2. Groth CG, Bäckman L, Morales J­M et al. Sirolimus (rapamycin)­based therapy in human renal transplantation. Transplantation 1999; 67: 1036--1042.

3. Sehgal SN. Rapamune ® (RAPA, rapamycin, sirolimus): Mechanism of action immunosuppressive effect results from blockade of signal transduction and inhibition of cell cycle progression. Clin Biochem 1998; 31: 335--340.

4. Kelly PA, Gruber SA, Behbod F et al. Sirolimus, a new, potent immunosuppressive agent. Pharmacotherapy 1997; 17: 1148--1156.

5. Kreis H, Cisterne J­M, Land W et al. Sirolimus in association with mycophenolate mofetil induction for the prevention of acute graft rejection in renal allograft recipients. Transplantation 2000; 69: 1252--1260.

6. Data on File, Wyeth­Ayerst Pharmaceuticals. (Johnson RWG, Kreis H, Oberbauer R et al. Sirolimus allows early cyclosporin withdrawal in renal transplantation resulting in improved renal function and lower blood pressure. Draft Manuscript, 11 January 2001)

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