Sirolimus and cyclosporine

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... 

Sirolimus and cyclosporine combination therapy Administer the initial dose as soon as possible after transplantation. For de novo transplant recipients, give a loading dose P.1151... 

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... 

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. 

Kaplan B, Meier-Kriesche HU, Napoli KL, Kahan BD. The effects of relative timing of sirolimus and cyclosporine microemulsion formulation coadministration on the pharmacokinetics of each agent. Clin Pharmacol Ther 1998 63 48-53. 

Lebranchu Y, Snanoudj R, Toupance O, Weestel PF, Hurault de Ligny B, Buchler M, et al. Five-year results of a randomized trial comparing de novo sirolimus and cyclosporine in renal transplantation the SPIESSER study. Am J Transplant July 2012 12(7) 1801-10. PubMed PMID 22486815. Epub 2012/04/11. eng. 

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. 

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. 

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. 

Seger C, Tentschert K, Stoggl W, Griesmacher A, Ramsay SL (2009) A rapid HPLC-MS/MS method for the simultaneous quantification of cyclosporine A, tacrolimus, sirolimus and everolimus in human blood samples. Nat Protoc 4 526-534... 

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. 

For a number of overt, broad spectrum immunosuppressive xenobiotics (e.g., azathioprine) there is sufficient clinical experience to indicate the types of neoplasms for which there is an increased risk. These tumor types are listed in Table 27.1. Also listed are the tumors that occur in the unfortunate experiment of nature, namely patients infected with human immunodeficiency virus type 1 (HIV-1) and the tumors that may occur at higher incidence with more selective yet strong immunosuppressants (e.g., cyclosporin, sirolimus, and tacrolimus). Compared to the broad spectrum immunosuppressive agents listed above, most IMBPs express a highly selective regulatory influence on the immune system modulating the activity of host defense systems rather than mediating frank immunosuppression. 

Zimmerman JJ, Harper D, Getsy J, Jusko WJ. Pharmacokinetic interactions between sirolimus and microemulsion cyclosporine when orally administered jointly and 4 hours apart in healthy volunteers. J Clin Pharmacol 2003 43(10) 1168-76. 

Streit F, Armstrong VW, OeUerich M. Rapid liquid chromatography-tandem mass spectrometry routine method for simultaneous determination of sirolimus, everolimus, tacrolimus, and cyclosporin A in whole blood. Clin Chem 2002 48 955-8. 

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 ... 

Cattaneo, D., Merlini, S., Zenoni, S., Balzelli, S., Gotti, E., Remuzzi, G., and Perico, N. (2005) Influence of comedication with sirolimus or cyclosporine on mycophenolic acid pharmacokinetics in kidney transplantation. American Journal of Transplantation, 5, 2937-2944. 

Sirolimus has been used to spare cyclosporine in the setting of cadaveric renal transplant since unlike the calcineurin inhibitors it is not vasoconstrictive and thus theoretically at least should be of benefit in ischemic reperfusion injury. The studies of Lieberthal mentioned above would lead one to a different strategy. Indeed there are now anecdotes appearing in the literature that similar to experimental animals, sirolimus potentiates ischemic injury following transplantation. There are few data with the combination of sirolimus and tacrolimus. However, limited information suggests that the pattern may be the same. Thus, it is clear that sirolimus used without a calcineurin inhibitor is safe from a nephrotoxic point of view but in combination with a calcineurin inhibitor there are either drug interactions or more fundamental cellular actions of sirolimus that may be adverse to renal tubular cells to impair recovery from ischemic insults such as hypotension and/or acute rejection episodes. 

Rapamycin (sirolimus) is another macrolide antibiotic that possesses potent immunosuppressant activity. Rapamycin has a chemical structure partially similar to that of tacrolimus (Fig. 2). It was first isolated from Streptomyces hygro-scopicus strains found in soil obtained on Rapa Nui (Easter Island), hence the name rapamycin [19, 20]. This compound was initially investigated as an antifungal agent and later found to have immunosuppressive activity [21]. Rapamycin also binds to FKBP, but its immunosuppressive mechanisms are distinct from those of tacrolimus and cyclosporin in that it does not act via the calcineurin pathway [22, 23]. The immunosuppressive effects of rapamycin result from its inhibition of T-cell [23, 24] and B-cell [25] proliferation. The key effect on those cells results from the blocking of the signals of several cytokines (IL-2 and IL-4), leading to interruption of the cell cycle from the G, to the S phase. Unlike tacrolimus, the complex of rapamycin and FKBP-12 does not inhibit the dephosphorylase... 

Therapy typically involves a calcineurin inhibitor (e.g., cyclosporine or tacrolimus), glucocorticoids, and mycophenolate mofetil (a purine metabolism inhibitor see below), each directed at a discrete site in T-cell activation. Alternatively, sirolimus can be used to limit exposure to the nephrotoxic calcineurin inhibitors. Glucocorticoids, azathioprine, cyclosporine, tacrolimus, mycophenolate mofetil, sirolimus, and various monoclonal and polyclonal antibodies are all approved for use in transplantation. 

Immune phillins Members of a highly conserved family of cytoplasmic proteins that bind to the immunosuppressants cyclosporine, tacrolimus, and sirolimus and assist these drugs in inhibiting T and B celi function. Cyclophilin binds cyclosporine, whereas FK-binding protein (FKBP) binds tacrolimus and sirolimus... 

Like tacrolimus, sirolimus binds to FKBP. However, unlike both tacrolimus and cyclosporine, sirolimus inhibits the response of T cells to cytokines without affecting cytokine production. Sirolimus has all of the other actions described. The answer is (B). 

Simultaneous Determination of Cyclosporine, Sirolimus, and Tacrolimus in Whole Blood Using Liquid Chromatography-Tandem Mass Spectrometry... 

Cyclosporine A (CSA), sirolimus, and tacrolimus are commonly used immunosuppressive drugs. Cyclosporine and tacrolimus are calcineurin inhibitors, whereas sirolimus is a mammalian target of rapamycin (mTOR) inhibitor. Calcineurin inhibitors bind to immunophilins, and drug-immunophilin complexes inhibit calcineurin activity, which in turn prevents nuclear translocation of the nuclear factor of activated T cells (NFAT) (1,2). This results in inhibition of activation and proliferation of CD4 and CDS lymphocytes by inhibiting IL-2 production. The mTOR protein is a... 

Table 4 MRMs for ascomycin, cyclosporine A, cyclosporine D, sirolimus and tacrolimus ...

Deters M, Kirchner G, Resch K, Kaever V (2002) Simultaneous quantification of sirolimus, everolimus, tacrolimus and cyclosporine by liquid chromatography-mass spectrometry (LC-MS). Clin Chem Lab Med 40 285-292... 

A number of fungal immunosuppressives have been isolated from fermentation broths and demonstrated to have immunotherapeutic efficacy. Other than cyclosporin (35), two fungal metaboHtes, sirolimus (36), previously known as rapamycin (80), and FK-506 (37) (81) are in various stages of development (see Antibiotics, macrolides). 

Immunosuppression induced by sirolimus (36) appears to be mediated by a mechanism distincdy different from that of either cyclosporin or FK-506. Sirolimus markedly suppresses IL-2 or IL-4-driven T-ceU proliferation. The preclinical studies suggest that sirolimus is a potent immunosuppressive agent in transplantation and autoimmune disease models. The clinical potential of this agent depends on its toxicity profile (80). 

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