Everolimus Cyclosporine

Deters M, Kirchner G, Koal T, Resch K, Kaever V. Everolimus/cyclosporine interactions on bile flow and biliary excretion of bile salts and cholesterol in rats. Dig Dis Sci 2004 49(l) 30-7. 

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... 

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. 

The initial success with sirolimus has led to the search of sirolimus analogs, Among these are everolimus (a new macrocylic triene derivative), ABT 578, and other antiimmunosuppressive compounds such as mycophenolic acid, cyclosporine, and tacrolimus, which inhibit proliferation via GI arrest and reduce the immune response. Data from animal experiments suggest that oral everolimus administered for one month effectively inhibits NIH (37) however, human trials have not been conducted. 

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... 

Kovarik JM, Kahan BD, Kaplan B, Lorber M, Winkler M, Rouilly M, Gerbeau C, Cambon N, Boger R, Rordorf C Everolimus Phase 2 Study Group. Longitudinal assessment of everolimus in de novo renal transplant recipients over the first post-transplant year pharmacokinetics, exposure-response relationships, and influence on cyclosporine. Clin Pharmacol Ther 2001 69(l) 48-56. 

Clinically important, potentially hazardous interactions with alfentanil, aminophylline, amisulpride, amoxicillin, ampicillin, anticonvulsants, astemizole, atorvastatin, benzodiazepines, bromocriptine, buprenorphine, bupropion, carbamazepine, cilostazol, ciprofloxacin, cisapride, clindamycin, colchicine, cyclosporine, dasatinib, digoxin, dihydroergotamine, diltiazem, disopyramide, enoxacin, eplerenone, ergotamine, eszopiclone, everolimus, fluconazole, fluoxetine, fluvastatin, gatifloxacin, HMG-CoA reductase inhibitors, imatinib, itraconazole, ketoconazole, lomefloxacin, lorazepam, lovastatin, methadone, methylprednisolone, methysergide, midazolam, mizolastine, moxifloxacin, nitrazepam, norfloxacin, ofloxacin, paroxetine, pimozide, pravastatin, quinolones, ranolazine, repaglinide, rupatadine, sertraline, sildenafil, simvastatin, sparfloxacin, sulpiride, tacrolimus, terfenadine, triazolam, troleandomycin, vardenafil, verapamil, vinblastine, warfarin, zaleplon, zolpidem, zuclopenthixol... 

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

Figure 33-13 Chemical structures of cyclosporine, sirolimus, tacrolimus, and everolimus.

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. 

Brignol, N. McMahon, L.M. Luo, S. Tse, RL.S. High-Throughput Semi-Automated 96-Well Liquid/Liquid Extraction and Liquid Chromatography/-Mass Spectrometric Analysis of Everolimus and Cyclosporin A in Whole Blood," Rapid Commun. Mass Spectrom. 15, 898-907 (2001). 

Kovarik JM, Kalbag J, Figueiredo J, Rouilly M, O Bannon LF, Rordorf C. Differential influence of two cyclosporine formulations on everolimus pharmacddnetics a clinically relevant pharmacokinetic interaction. J CUn Pharmacol (2002) 42,95-9. 

Favi E, Spagnoletti G, Salerno MP, Pedroso JA, Romagnoli J, Citterio F. Tacrolimus plus mycophenolate mofetil vs cyclosporine plus everolimus in deceased donor kidney transplant recipients three-yr results of a single-center prospective clinical trial, din Transplant 2013 Jul-Aug 27(4) E359-67. PubMed PMID 23710603. Epub 2013/05/29. eng. 

Sirolimus (rapamycin) (Vezina et al. 1975) is widely used to prevent rejection in organ transplant. It is especially usefiil in kidney transplants because, different from cyclosporine and tacrolimus, it is not a calcineurin inhibitor and therefore is less toxic to the kidney. Sirolimus inhibits T-cell and B-cell activation. It binds to the immunophilin FKproteinl2, and this binary complex inactivates a serine-threonine kinase (mTOR) termed the mammalian target of rapamycin (Huang et al. 2003). The final effect is the arrest at phase G1 of cell cycle progression. This effect occurs not only in T cell and B cells, but it has been observed in many tumor cell lines. Semisynthetic derivatives of rapamycin, suitable for i.v. administration, have been developed as antitumor agents. Temsirolimus was approved by FDA in 2007 for advanced kidney cancer treatment (Hudes 2009). Everolimus was also approved for kidney cancer treatment in 2009 and for organ rejection prophylaxis in 2010. At present, phase III clinical trials are under way in a variety of tumors (Dansey 2006). 

---