Sirolimus with cyclosporine

Barten MJ, Streit F, Boeger M, et al. Synergistic effects of sirolimus with cyclosporine and tacrolimus analysis of immunosuppression on lymphocyte proliferation and activation in rat whole blood. Transplantation 2004 77(8) 1154-62. 

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 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... 

Substrates of the CYP3A4 isozyme will compete with cyclosporine, tacrolimus, and sirolimus for metabolism therefore, concentrations of both medications may be increased (usually by less than or equal to 20%). bnducers of the CYP3A4 isozyme will enhance the metabolism of cyclosporine, tacrolimus, and sirolimus therefore, concentrations of these medications may be decreased. 

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... 

In this and another study in de novo liver transplant recipients, the use of sirolimus in combination with cyclosporine or tacrolimus was associated with an increase in HAT most cases of HAT occurred within 30 days post-transplantation and most led to graft loss or death. 

Organ rejection Prophylaxis of organ rejection in patients receiving renal transplants. It is recommended that sirolimus be used in a regimen with cyclosporine and corticosteroids. In patients at low to moderate immunological risk, cyclosporine should be withdrawn 2 to 4 months after transplantation and sirolimus dose should be increased to reach recommended blood concentrations. 

Concurrent immunosuppressants Sirolimus has been administered concurrently with cyclosporine and corticosteroids. The efficacy and safety of the use of sirolimus in combination with other immunosuppressive agents have not been determined. Renai function impairment Mean serum creatinine was increased and mean glomerular filtration rate was decreased in patients treated with sirolimus and cyclosporine compared with those treated with cyclosporine and placebo or azathioprine controls. Monitor renal function during the administration of maintenance immunosuppression regimens including sirolimus in combination with cyclosporine, and consider appropriate adjustment of the immunosuppression... 

Sirolimus (Rapamune) is structurally related to tacrolimus. It is approved for use as an adjunctive agent in combination with cyclosporine for prevention of acute renal allograft rejection. It blocks IL-2-dependent T-cell proliferation by inhibiting a cytoplasmic serine-threonine kinase. This mechanism of action is different from those of tacrolimus and cyclosporine. This allows sirolimus to augment the immunosuppressive effects of these drugs. 

The serious side effects of sirolimus may include an allergic reaction, increased risk of infection and lymphoma. Nephrotoxicity is not a concern when the drug is not used in combination with cyclosporine or tacrolimus. Less serious side effects associated with the administration of sirolimus include stomach upset, increased cholesterol and triglyceride levels, acne, insomnia, tremor, sore or weak muscles,... 

Chueh SC, Kahan BD. Dyslipidemia in renal transplant recipients treated with a sirolimus and cyclosporine-based immunosuppressive regimen incidence, risk factors, progression, and prognosis. Transplantation 2003 76 375-82. 

Groth CG, Backman L, Morales JM, Caine R, Kreis H, Lang P, Touraine JL, Claesson K, Campistol JM, Durand D, Wramner L, Brattstrom C, Charpentier B. Sirohmus (rapamycin)-based therapy in human renal transplantation similar efficacy and different toxicity compared with cyclosporine. Sirolimus European Renal Transplant Study Group. Transplantation 1999 67(7) 1036-42. 

Toxicity The use of sirolimus in renal transplant patients is associated with a dose-dependent increase in serum cholesterol and triglycerides. While immunotherapy with sirolimus per se is not nephrotoxic, patients treated with cyclosporine plus sirolimus have impaired renal function compared to patients treated with cyclosporine alone. Sirolimus also may prolong delayed graft... 

Clinical uses and pharmacokinetics Use of these immunosuppressants is a major factor in the success of solid organ transplantation. Cyclosporine is used in solid organ transplantation and in graft-versus-host syndrome in bone marrow transplants. Tacrolimus is used in liver and kidney transplant recipients and may be effective as rescue therapy in patients who fail standard therapy. Sirolimus is used alone or in combination with cyclosporine in kidney and heart transplantation. The agents, particularly cyclosporine, may also be effective in immune diseases, including rheumatoid arthritis, uveitis, psoriasis, asthma, and type 1 diabetes. 

Buchler M, Lebranchu Y, Beneton M, Le Meur Y, Heng AE, Westeel PF, le Guellec C, Libert F, Hary L, Ivferquet P, Paintaud G. Higher ej osure to mycophenoUc acid with sirolimus than with cyclosporine cotreatment. CUn Pharmacol 77 er(2005) 78,34-42. 

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. 

Cytokines. Figure 1 Inhibition of cytokine synthesis during activation of the specific immune system. The monoclonal antibodies Muromonab and Basiliximab are specific for the CD3 complex of the T-cell receptor, and for the IL-2 receptor on lymphocytes, respectively. Cyclosporin and Tacrolimus inhibit activation of cytoplasmic NF-AT, a transcription factor essential for activation of the IL-2 gene ( NFAT Family of Transcription Factors). Sirolimus interferes with mTOR signaling and inhibits IL-2 dependent proliferation. Red pharmaka, blue target proteins. 

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... 

Although tacrolimus therapy is associated with increasing blood pressure, studies have found that tacrolimus has less dramatic effects on GFR and RBF than cyclosporine. In some clinical trials, tacrolimus caused less severe HTN and required significantly fewer antihypertensive medications at both 24 and 60 months after transplantation than cyclosporine.61-63 Thus conversion from cyclosporine-based immunosuppression to tacrolimus-based immunosuppression may be one way to minimize blood pressure increases in transplant recipients. Conversion to sirolimus also may be an alternative to the calcineurin inhibitors in patients with difficult-to-treat HTN because sirolimus therapy is less associated with increased blood pressure. Additionally, withdrawal or tapering of steroid therapy may be an effective strategy for lowering blood pressure. 

Koal et al. (2004) measured four immunosuppressants (cyclosporine A, tacrolimus, sirolimus, and everolimus) in whole blood samples from transplant recipients. The samples were treated first with a protein precipitation step. The supernatant was extracted with a Poros Rl/20 perfusion column (30 x 2.1 mm, 20 tm, Applied Biosystems, Darmstadt, Germany) online. A Luna phenyl hexyl column (2 x 50 mm, Phenomenex, Schaffenburg, Germany) was used for separation. The total run time was 2.5 min. The lower limit of quantitation was 10 ng/mL for cyclosporine A and 1 ng/mL for the other three analytes. 

Ceglarek et al.45 reported the rapid simultaneous quantification of immmunosuppressants (cyclosporine A, tacrolimus, and sirolimus) in transplant patients by turbulent flow chromatography (TFC) coupled with HPLC-MS/MS. TFC is an online extraction technique involving the direct application of human plasma onto a turbulent flow column where protein is washed from the samples before the retained drug is backflushed onto an analytical column. 

Rapamycin, also known as sirolimus, is a new macrolide antibiotic that interacts with cellcycle regulating proteins and inhibits cell division. The main side effects are thrombocytopenia and hyperlipidaemia. There is also evidence that it causes interstitial pneumonitis, which may resolve on withdrawing the drug or dose reduction. The drug is currently being assessed for combination therapy with tacrolimus or cyclosporin. 

Sirolimus has been used effectively alone and in combination with other immunosuppressants (corticosteroids, cyclosporine,... 

To minimize the variability of blood concentrations, sirolimus should be taken consistently in relation to time of administration with or without cyclosporine and/or food. 

Sirolimus tablets - For simultaneous administration, mean C and AUC were increased by 512% and 148%, respectively, relative to administration of sirolimus alone. However, when given 4 hours after cyclosporine administration, sirolimus C and AUC were both increased by only 33% compared with administration of sirolimus alone. 

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. 

---