Sirolimus and tacrolimus

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. 

Paramesh AS, Grosskreutz C, Florman SS, Gondolesi GE, Sharma S, Kaufman SS, Fishbein TM.Thrombotic microangiopathy associated with combined sirolimus and tacrolimus immunosuppression after intestinal transplantation. Transplantation 2004 77 129-131. 

Considerable attention is paid to validation of the analytical results. Typical linear dynamic ranges are 0.2-100 pg/1 for sirolimus and tacrolimus, and 1-1000... 

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 ... 

Pham SM, Qi XS, Mallon SM, et al. Sirolimus and tacrolimus in clinical cardiac transplantation. Transplant Proc 2002 34 1839-1842. 

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. 

There is an isolated case report of increased sirolimus and tacrolimus levels associated with the concurrent use of amiodarone in a paediatric patient. 

The authors of this report advise that, because of the long half-life of sirolimus, and the difficulty in reducing elevated levels quickly, prescrib-ers should consider reducing the sirolimus and tacrolimus doses before starting amiodarone rather than waiting for the interaction to occur. They also advise more frequent monitoring of sirolimus and tacrolimus levels if amiodarone is also given. This appears to be the only published report of this interaction at present. 

Patat A, Zimmerman JJ, Parks V, Souan M Lack of pharmacokinetic interaction co-adminis-tered of sirolimus and tacrolimus Clin Pharmacol Ther (2003) 73, P43... 

Alfadhli E, Koh A, Albaker W, Bhargava R, Ackerman T, McDonald C, Ryan EA, Shapiro AM, Senior PA. High prevalence of ovarian cysts in premenopausal women receiving sirolimus and tacrolimus after clinical islet transplantation. Transpl Int 2009 22(6) 622-5. 

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... 

The commonly used methods for the determination of these drugs are immunoassays and chromatography. Most immunoassays for immunosuppressants are semiautomated since extraction of drugs from the whole blood is needed before analysis. Immunoassays are convenient due to automation, but have problems with cross-reactivity with drug metabolites (3, 6). Both polyclonal and monoclonal antibody-based assays are available. Monoclonal antibody-based immunoassays are more specific. HPLC with ultraviolet detection and tandem mass spectrometry are commonly used chromatographic methods for the assay of immunosuppressants. Due to their specificity and sensitivity, tandem mass spectrometry assays are preferred and are now in wide use (7, 8). The other major advantage of tandem mass spectrometry assays is their ability to simultaneously measure several immunosuppressants (7-10). Pharmacokinetic properties of CSA, sirolimus, and tacrolimus are shown in Table 1 (3, 6, 11). 

Stock standards Add 1 mL each of 1 mg/mL primary standards of CSA, sirolimus, and tacrolimus to separate 10 mL volumetric flasks and fill to the mark with methanol. This provides the final concentration of 100 pg/mL for each standard. 

Working standards mixture Add 1.25 mL CSA, 125 pL sirolimus and 125 pL tacrolimus stock standards to a 250 mL volumetric flask, and bringing the volume to the mark with drug-free whole blood. Final concentrations of CSA, sirolimus, and tacrolimus are 500, 50, and 50 ng/mL, respectively. 

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

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