Mycophenolate Sirolimus

Clinically important, potentially hazardous interactions with azathioprine, basiliximab, corticosteroids, cyclosporine, daclizumab, glatiramer, mycophenolate, sirolimus, tacrolimus... 

The body s immune response is suppressed by immunosuppressants such as ciciosporin, mycophenolate, sirolimus, and tac-roiimus. The antibody response to vaccines may be reduced, aithough even partiai protection may be of benefit In general, the use of iive attenuated vaccines is considered contraindicated because of the possible risk of generaUsed infection. Inactivated vaccines may be used. 

FK-506 (37) interferes with IL-2 synthesis and release and has a cyclosporin-like profile, but is considerably more potent in vitro. IC q values are approximately 100-fold lower. This neutral macroHde suppresses the mixed lymphocyte reaction T-ceU proliferation generation of cytotoxic T-ceUs production of T-ceU derived soluble mediators, such as IL-2, IL-3, and y-IFN and IL-2 receptor expression (83). StmcturaHy, FK-506 is similar to sirolimus. Mycophenolate mofetil (33), brequinar (34), and deoxyspergualin are in various phases of clinical evaluation. Identification of therapeutic efficacy and safety are important factors in the deterrnination of their utiUty as immunosuppressive agents. 

FIGURE 52-2. Center-specific protocols may use RATG, an IL-2RA, or no induction therapy. In any situation, patients receive IV methylprednisolone prior to, during, or immediately following the transplant operation. The patient then will begin the maintenance immunosuppressive regimen. The center-specific protocol will specify which calcineurin inhibitor (cyclosporine or tacrolimus) is used in combination with mycophenolate mofetil or sirolimus with or without steroids. Patients then are monitored for signs and symptoms of rejection. 

These agents generally are considered to be adjuvant to the calcineurin inhibitors or possibly sirolimus. The antiproliferatives azathioprine and the mycophenolic acid (MPA) derivatives inhibit T cell proliferation. 

Sirolimus is currently the only FDA-approved ToR inhibitor. One of its derivatives, everolimus, is in phase III clinical trials and has been approved for use in some European countries.30 Sirolimus is a macrolide antibiotic that has no effect on cal-cineurin phosphatase.11,31,32 Sirolimus inhibits T cell activation and proliferation by binding to and inhibiting the activation of the mammalian ToR, which suppresses cellular response to IL-2 and other cytokines (i.e., IL-4 and IL-15J.11,31 Studies have shown that sirolimus may be used safely and effectively with either cyclosporine or tacrolimus as a replacement for either azathioprine or mycophenolate mofetil.33 However, when using both sirolimus and cyclosporine as part of a patient s immunosuppressant therapy, because of a drug interaction between the two resulting in a marked increase in sirolimus concentrations, it is recommended to separate the sirolimus and cyclosporine doses by at least 4 hours. Sirolimus also can be used as an alternative agent for patients who do not tolerate calcineurin inhibitors due to nephrotoxicity or other adverse events.34... 

Azathioprine, mycophenolate mofetil, and enteric-coated MPA are not metabolized through the CYP isozyme system therefore, they do not experience the same DDI profiles as cyclosporine, tacrolimus, and sirolimus. Azathioprine s major DDIs involve allopurinol, angiotensin-converting enzyme (ACE) inhibitors, aminosalicylates (e.g., mesalamine and sulfasalazine), and warfarin.11 The interaction with allopurinol is seen frequently and has clinical significance. Allopurinol inhibits xanthine oxidase, the enzyme responsible for metabolizing azathioprine. Combination of azathioprine and allopurinol has resulted in severe toxicities, particularly myelosuppression. It is recommended that concomitant therapy with azathioprine and allopurinol be avoided, but if combination therapy is necessary, the azathioprine doses must be reduced to one-third or one-fourth of the current dose. Use of azathioprine with the ACE inhibitors or aminosalicylates also can result in enhanced myelosuppression.11 Some case reports exist demonstrating that warfarin s therapeutic effects may be decreased by azathioprine.43-45... 

Cattaneo D, Merlini S, Zenoni S, Baldelli S, Gotti E, Remuzzi G Perico N. (2005) Influence of co-medication with sirolimus or cyclosporine on mycophenolic acid pharmacokinetics in kidney transplantation. Am J... 

Selective immunosuppressive agents mycophenolate mofetil sirolimus tacrolimus... 

Methyl prednisolone Muromonab-CD3 Mycophenolate Mofetil Prednisone Tacrolimus Basiliximab Daclizumab Sirolimus... 

Sirolimus is used for tissue transplantation where its major advantage over calci-neurin inhibitors is that it is not nephrotoxic. Chronic renal failure in transplant patients who have taken calcineurin inhibitors for the long term can be prevented by the administration of sirolimus. Steroid-free immunosuppression can be achieved by administering sirolimus alone or in combination with mycophenolate mofetil and cyclosporine or tacrolimus. Since impaired wound healing is one of its potential side effects, some transplant centers use sirolimus only after several weeks of surgery. 

Mycophenolate mofetil is used for tissue transplantation in combination with tacrolimus or cyclosporine or sirolimus plus glucocorticoids. It is used more than any other cytotoxic drug either at the time of the transplant or following the initiation of acute rejection. Mycophenolate mofetil is a prophylactic agent and cannot be used for chronic rejection or ongoing acute rejection. 

Azathioprine is administered to patients who do not respond to calcineurin inhibitors, sirolimus and glucocorticoids. Daily doses of 3-10 mg/kg of azathioprine are administered 1 or 2 days before renal transplantation or on the day of surgery for prophylactic therapy. Mycophenolate mofetil is increasingly used in place of azathioprine for tissue transplantation since it is less myelotoxic and causes few opportunistic infections. 

Grinyo JM, Cruzado JM. 2006. Mycophenolate mofetil and sirolimus combination in renal transplantation. Am J Transplant. 6 1991-1999. 

Tacrolimus + sirolimus, tacrolimus + mycophenolate mofetil, and ciclosporin + sirolimus have been compared in recipients of their first kidney transplant (52). One-year patient and graft survival did not differ. Ciclosporin + sirolimus was associated with increased serum creatinine concentrations, reduced creatinine clearance, more frequent protocol discontinuation, more antihyperlipidemic drug therapy, and a higher incidence of post-transplant diabetes mellitus. 

Ciancio G, Burke GW, Gaynor JJ, Mattiazzi A, Roth D, Kupin W, Nicolas M, Ruiz P, Rosen A, Miller J. A randomized long-term trial of tacrolimus/sirolimus versus tacro-limus/mycophenolate mofetil versus cyclosporine (NEORAL)/sirolimus in renal transplantation. II. Survival, function, and protocol compliance at 1 year. Transplantation 2004 77(2) 252-8. 

The initial success with sirolimus has led to the search of sirolimus analogs, Among these are everolimus (a new macrocylic triene derivative), ABT 578, and other antiimmunosuppressive compounds such as mycophenolic acid, cyclosporine, and tacrolimus, which inhibit proliferation via GI arrest and reduce the immune response. Data from animal experiments suggest that oral everolimus administered for one month effectively inhibits NIH (37) however, human trials have not been conducted. 

Picard N, Premaud A, Rousseau A, et al. A comparison of the effect of ciclosporin and sirolimus on the pharmokinetics of mycophenolate in renal transplant patients. Br J Clin Pharmacol 2006 62(4) 477 484. 

Cyclosporine is an important drug in preventing rejection after kidney, hver, heart and other organ transplantation (Haberal et al., 2004). Cyclosporine usually is combined with other immunosuppressives especially glucocorticoids and either azathioprine or mycophenolate mofedl and sirolimus (Krensky et al., 2005). In renal alio transplants it has improved graft acceptance in most clinics to 95 percent. In addition to its use in transplantation cyclosporine is used for the treatment of a number of autoimmune diseases. In autoimmune diseases, as might be anticipated, cyclosporine is most effective in those which are T cell mediated. These include several forms of psoriasis, rheumatoid arthritis refractive to all other therapy, uveitis, nephrotic syndrome and type I diabetes mellitus. 

Sirolimus is used for the prophylaxis of organ transplant rejection in combination with a calcineurin inhibitor and glucocorticoid. In patients at high risk for nephrotoxicity it has been combined with glucocorticoids and mycophenolate to avoid permanent renal damage (Kahan and Camardo, 2001). 

Attempts to minimize TAC-induced renal dysfunction by TAC switch to sirolimus [419, 744, 745] or use of low-dose maintenance TAC therapy associated with lymphocyte depleting agents, mycophenolate mofetil or sirolimus have been successfully achieved [746-750]. However, the association of TAC and sirolimus does not seem to be problem-free. Severe acute kidney injury in renal transplant recipients and thrombotic microangiopathy in intestinal transplant have been associated to combined use of TAC and sirolimus [751, 752], renal function improved in renal transplant recipients after conversion from TAC/ sirolimus to TAC/MMF therapy [753] and TAC/sirolimus combination was associated to worst renal allograft survival than TAC/MMF im-... 

Pescovitz MD, Govani M. Sirolimus and mycophenolate mofetil for calcineurin-free immunosuppression in renal transplant recipients. Am J Kidney Dis 2001 38 S16-S21. 

Augustine JJ, Chang PC, KnaussTC, Aeder Ml, BodziakKA, SchulakJA, HricikDE. Improved renal function after conversion from tacrolimus/sirolimus to tacrolimus/mycophenolate mofetil in kidney transplant recipients. Transplantation 2006 81 1004-1009. 

Meier-Kriesche HU, Schold JD, SrinivasTR, Howard RJ, Fujita S, Kaplan B. Sirolimus in combination with tacrolimus is associated with worse renal allograft survival compared to mycophenolate mofetil combined with tacrolimus. Am J Transplant 2005 5 ... 

Immunosuppressive drugs can be divided into five basic categories. Corticosteroids such as methylprednisolone and prednisone are a part of virtually all immunosuppressive drug regimens. Corticosteroids block the production of IL-1 and have potent anti-inflammatory effects. Calcineurin inhibitors such as cyclosporine and tacrolimus are also used in a majority of immunosuppressive drug regimens. Calcineurin inhibitors inhibit the production and secretion of IL-2. IL-2 is involved with T-lymphocyte activation and proliferation. Antiproliferative agents such as azathioprine, mycophenolate mofetil, and sirolimus block T-lymphocyte... 

Clinically important, potentially hazardous interactions with amiloride, aminoglycosides, amphotericin B, ampicillin, anisindione, anticoagulants, armodafinil, atorvastatin, azathioprine, azithromycin, bacampicillin, basiliximab, bezafibrate, bosentan, bupropion, carbenicillin, caspofungin, cholestyramine, clarithromycin, cloxacillin, co-trimoxazole, corticosteroids, cyclophosphamide, daclizumab, danazol, dicloxacillin, dicumarol, digoxin, diltiazem, disulfiram, echinacea, erythromycin, ethotoin, etoposide, ezetimibe, flunisolide, fluoxymesterone, fluvastatin, foscarnet, fosphenytoin, gemfibrozil, hemophilus B vaccine, HMG-CoA reductase inhibitors, imatinib, imipenem/cilastatin, influenza vaccines, ketoconazole, lanreotide, lopinavir, lovastatin, mephenytoin, methicillin, methoxsalen, methylphenidate, methylprednisolone, methyltestosterone, mezlocillin, mizolastine, mycophenolate, nafcillin, nisoldipine, NSAIDs, orlistat, oxacillin, penicillins, phellodendron, phenytoin, pravastatin, prednisolone, prednisone, pristinamycin, ranolazine, red rice yeast, rifabutin, rifampin, rifapentine, ritonavir, rosuvastatin, simvastatin, sirolimus, spironolactone, St John s wort, sulfacetamide, sulfadiazine, sulfamethoxazole, sulfisoxazole, sulfonamides, tacrolimus, telithromycin, tenoxicam, testosterone, ticarcillin, tolvaptan, trabectedin, triamterene, troleandomycin, ursodeoxycholic acid, vaccines, vecuronium, warfarin, zofenopril... 

Outpatient immunosuppressive medications—most commonly, azathioprine, cyclosporine, mycophenolate, prednisone, sirolimus, and tacrolimus—are covered by Medicare Part B. Currently, medicare pays for 80% of immunosuppressive drug therapy. The other 20% is the patient s responsibility. To qualify for Medicare immunosuppressive coverage, the patient must have the following ... 

RATG = rabbit antithymocyte immunoglobulin IL2RA = interleukin-2 receptor antagonist Cl = calcineurin inhibitor CSA = cyclosporine TAC = tacrolimus MMF = mycophenolate mofetil SRL = sirolimus BUN =blood urea nitrogen SCr = serum creatinine LFTs = liver function tests OKT3 = muromonab CD3. 

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