Sirolimus interactions

Perron GM, Jusko WJ. Species- and gender-related differences in cyclosporine/prednisolone/sirolimus interactions in whole blood lymphocyte proliferation assays. J Pharmacol Exp Ther 1998 286 191-200. 

Anglicheau D, Pallet N, Rabant M, Marquet P, Cassinat B, Meria P, Beaune P, Legendre C, Thervet E. Role of P-glycoprotein in cyclosporine cytotoxicity in the cyclosporine-sirolimus interaction. Kidney Int 2006 70 1019-1025. 

Drug Interactions Since sirolimus is a substrate for CYP3A4 and is transported by P-glycoprotein, close attention to interactions with other drugs that are metaboUzed or transported by these proteins is required. As noted above, cyclosporine and sirolimus interact, and their administration should be separated by time. Dose adjustment may be required when sirolimus is coadministered with diltiazem or rifampin. 

D browska-Zamojcin E, Pawlik A, Domahski L, RoZahski J, Droidzik M. Cyclosporine and sirolimus interaction in a kidney transplant patient. Transplant Proc (2005) 37, 2317-19. 

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... 

TABLE 52-6. Potential Drug-Drug Interactions with the Calcineurin Inhibitors and Sirolimus Mediated Through the CYP3A4 Isozyme11... 

Drug/Food interactions To minimize variability, sirolimus should be taken consistently with or without food (see Administration and Dosage). 

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. 

Micafungin, anidulafungin Micafungin increases levels of nifedipine, cyclosporine, sirolimus anidulafungin is relatively free of this interaction ... 

Metabolism inducible. Susceptible to inhibition of metabolism by CYP3A4. (Tacrolimus and sirolimus appear to have similar interactions.)... 

BottigerY Sawe J, Brattstrom C, et al. Pharmacokinetic interaction between single oral dose of diltiazem and sirolimus in healthy volunteers. Cli Pharmacol 2001 69 32-40. 

TRASTUZUMAB CICLOSPORIN, SIROLIMUS t neutropenic effect of immunosuppressants Additive effects Warn patients to report symptoms such as sore throat and fever >- For signs and symptoms of neutropenia, see Clinical Features of Some Adverse Drug Interactions, Immunosuppression and blood dyscrasias... 

The pharmacokinetic interaction of a single oral dose of diltiazem 120 mg with a single oral dose of sirolimus 10 mg... 

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. 

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