Tacrolimus with mycophenolate mofetil

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. 

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. 

Daclizumab is used for the prophylaxis of acute rejection in patients receiving kidney transplants. A dose of 1 mg/kg is sufficient to completely block all the IL-2 receptors. It is administered in five doses at a 2-week interval where its elimination half-life is about 20 days. A combination of several other immunosuppressive agents including cyclosporine (or tacrolimus, rapamycin), mycophenolate mofetil and corticosteroids can be used with daclizumab. When it is used in combination with tacrolimus, the doses of tacrolimus are reduced. After tissue transplantation, the addition of daclizumab to the standard immunosuppressive regimen produces reduction in tissue rejection up to 50%. Daclizumab can cause hypersensitivity reactions, but it does not cause cytokine-release syndrome. There is a low incidence of... 

Pergola PE, Kancharla A, Riley DJ. Kidney transplantation during the first trimester of pregnancy immunosuppression with mycophenolate mofetil, tacrolimus, and prednisone. Transplantation 2001 71(7) 994-7. 

The principal toxicities of mycophenolate are gastrointestinal and hematologic. These include leukopenia, diarrhea, and vomiting. There also is an increased incidence of some infections, especially sepsis associated with cytomegalovirus. Tacrolimus in combination with mycophenolate mofetil has been associated with devastating viral infections including polyoma nephritis. 

Observational studies In a retrospectively analysed prospective study in seven patients with lupus nephritis who had failed on mycophenolate mofetil monotherapy, toxicity limited the use of combination therapy of tacrolimus-I-mycophenolate mofetil [84 ]. One patient achieved a complete renal remission, while three had partial remissions, with reductions in proteinuria. Four of seven patients stopped taking combination therapy because of diabetic ketoacidosis (n = l), pneumonia (n — 1) and muscle pain (n = 2). Four had infectious complications, pneumonia (n = 2), herpes zoster ( = 1), and septic arthritis (n = l). There were no severe nephrotoxic adverse reactions, although there was a small increase in serum creatinine in two patients. 

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... 

Systemic therapies are seldom used for mild to moderate psoriasis, and are generally reserved for patients with moderate to severe psoriasis.17 29 Oral agents include sulfasalazine, acitretin, methotrexate, cyclosporine, mycophenolate mofetil, azathioprine, tacrolimus, and hydroxyurea. Parenteral agents include the biologic response modifiers alefacept, efalizumab, etanercept, infliximab, and many others, currently at various stages of research or approval for psoriasis. 

Budde K, Glander P, Grohmann J, Bauer S, Hambach P, Hepburn H, Mai I, Sandau K, Fischer W, Neumayer HH. (2004) Pharmacokinetic and pharmacodynamic comparison of mycophenolate mofetil (MMF) and enteric-coated mycophenolate sodium (EC-MPS) in maintenance renal transplant patients with tacrolimus as basic immunosuppression (P736). Transplantation 78 459 60. 

The metabolism of mycophenolate is altered by coadministration with cyclosporine. Mycophenolic acid (MPA) levels are lower when mycophenolate mofetil is compared with cyclosporine. Lower doses should be considered in recipients receiving tacrolimus or steroids done without a calcineurin inhibitor. 

Recent data from a kidney pancreas induction study suggests that 2 doses of Daclizumab (2 mg/kg) at day 0 and day 14 is equivalent to 5 doses of 1 mg/kg every 14 days. (Stratta AJ, Alloway RR, Hodge E et al. A multicenter, open-label, comparative trial of two Daclizumab dosing strategies vs. no antibody induction in combination with tacrolimus, mycophenolate mofetil, and steroids for the prevention of acute rejection in simultaneous kidney-pancreas transplant recipients interim analysis. Clin Transplant 2002 l6(l) 60-8.)... 

The coadministration of mycophenolate mofetil with antacids results in decreased absorption. The plasma MPA concentration is significantly reduced by cholestyramine due to binding of the cholestyramine to MPAG in the intestine and interfering with the enterohepatic recirculation of the drug. The bioavailability of mycophenolate mofetil is higher when administered with tacrolimus as opposed to cyclosporine. The bioavailability of MPA is reduced by antibiotics including fluoroquinolones and metronidazole. 

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. 

Boratynska M, Banasik M, Patrzalek D, Klinger M. 2006. Conversion from cyclosporine-based immunosuppression to tacrolimus/mycophenolate mofetil in patients with refractory and ongoing acute renal allograft rejection. Ann Transplant. 11 51-56. 

Tanabe K, Tokumoto T, Ishida H, Ishikawa N, et al. 2004. Excellent outcome of ABO-incompatible living kidney transplantation under pre transplantation immunosuppression with tacrolimus, mycophenolate mofetil and steroid. Transpl Proc. 36 2175-2177. 

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. 

A 47-year-old multiparous Hispanic woman received a living-unrelated kidney transplant for end-stage renal disease secondary to polycystic kidney disease. On the day of transplantation she received intravenous daclizumab 1 mg/kg plus methylprednisolone 300 mg and mycophenolate mofetil 3 g/day, and on day 3 ciclosporin emulsion 4 mg/kg/day. On day 8 she developed thrombotic microangiopathy without evidence of rejection. Ciclosporin was withdrawn. Plasmapheresis with fresh frozen plasma was started. Daclizumab on day 14 was postponed for 24 hours and plasmapheresis was stopped to avoid clearance of daclizumab. Thereafter she was given tacrolimus, without recurrence of hemolysis. 

In 11 patients with orthotopic hver transplants who had adverse effects from ciclosporin or tacrolimus, mycophenolate mofetil monotherapy for 1 year was successful. This was followed by a randomized, controlled trial in 18 patients, of whom nine were given mycophenolate mofetil (23). Five patients completed the 3 month trial. Of these, two had an episode of acute rejection, one after 2 months and one after 3 months, which did not respond to the reintroduction of tacrohmus and intravenous glucocorticoids. One had a glucocorticoid-responsive episode of severe acute rejection after 3 weeks. The other two patients had normal liver function tests after 2 weeks and 2 months respectively, when the trial was stopped. Mycophenolate mofetil allows a reduction of the dose of... 

Shapiro R, Jordan ML, Scantlebury VP, Vivas C, Gritsch HA, CasaviUa FA, McCauley J, Johnston JR, Randhawa P, Irish W, Hakala TR, Fung JJ, Starzl TE. A prospective, randomized trial to compare tacrolimus and prednisone with and without mycophenolate mofetil in patients undergoing renal transplantation first report. J Urol 1998 160(6 Pt l) 1982-6. 

Jain A, Mohanka R, Orloff M, Abt P, Kashyap R, Kelley M, Burlee K, Bozorgzadeh A. Intravenous mycophenolate mofetil with low-dose oral tacrolimus and steroid induction for live donor liver transplantation. Exp Clin Transplant 2005 3 361-365. 

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... 

---