Sirolimus

Mamalian Target of Rapamycin inhibitor Sirolimus

Contents ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

Most isolated island in the world Located about 2400 Km from both Tahiti and Chile Today, the land, people, and Language is referred as “RAPA NUI” Rapa was found in Easter Island Rapa Nui - Island flag http://en.wikipedia.org/wiki/Easter_island

Pharmacology Pharmacokinetics Pharmacodynamics Sirolimus

Structure and mechanism of action Sirolimus

Systematic (IUPAC) name (3S,6R,7E,9R,10R,12R,14S,15E,17E,19E,21S,23S, 26R,27R,34aS)-9,10,12,13,14,21,22,23,24,25,26, 27,32,33,34,34a-hexadecahydro-9,27-dihydroxy-3- [(1R)-2-[(1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl]- 1-methylethyl]-10,21-dimethoxy-6,8,12,14,20,26- hexamethyl-23,27-epoxy-3H-pyrido[2,1-c][1,4]- oxaazacyclohentriacontine-1,5,11,28,29 (4H,6H,31H)-pentone http://en.wikipedia.org/wiki/Rapamycin ,[object Object],[object Object],[object Object],[object Object]

Mechanism of action ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],Galat A, Metcalf S. Prog in Biophys Mol Bio . 1995 Wiederrecht G, et al. Progress in Cell Cycle Research . 1995 Liu J, et al. Cell . 1991 Flanagan WM, et al. Nature . 1991 McCaffrey PG, et al. J Biol Chem . 1993

mTOR Is a Critical Kinase in Cell Cycle Progression Adapted from Wyeth Research. Subcommittee of the Antiviral Advisory Committee on Immunosuppressive Drugs. Jan 24, 2002 p70 S6 kinase Ribosome Protein synthesis S6 DNA synthesis Cyclin E cdk2 P27 P P Translation activation eIF-4E phas-1 mTOR IL-2, IL-15 Co-stimulatory pathway FKBP12 RAPA

Effects of Sirolimus on T Cells, B Cells, and Smooth Muscle Cells 16 CELL STIMULUS FUNCTION T Cell B Cell Mitogen antigen anti-CD3, CD28 IL-2, 15 IL-2, 3, 4, 5, GM-CSF, INF-  IL-4 Pokeweed mitogen, anti-Ig, LPS IgE Y Y Y IgA IgM IgG SMC fibroblasts Growth factors Migration Y = FKBP 12: Sirolimus/TOR complex

FKBP ,[object Object],[object Object],[object Object],[object Object]

Mammalian target of rapamycin ,[object Object],[object Object],[object Object],[object Object],http://en.wikipedia.org/wiki/Mammalian_target_of_rapamycin mTOR has been shown to function as the catalytic subunit of two distinct molecular complexes in cells.

mTOR has been shown to function as the catalytic subunit of two distinct molecular complexes in cells.

Sirolimus Demonstrates Anti-Proliferative Activity Against a Variety of Cell Types ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],Chen J et al. Proc Am Assoc Cancer Res . 1997;38:63-64. Cao W, et al. Transplantation. 1995;59:390-395. Marx SO, et al. Circ Res. 1995;76:412-417. Nair RV, et al. Transplant Proc. 1997;29:614-615. Mohacsi PJ et al. J Heart and Lung Transplant. 1997;16:484-492.

Effect of Sirolimus on Apoptosis ,[object Object],[object Object],[object Object],Dai Z, et al. J. Immunol. 1998;161:1659-1663. Shi Y, et al. Nature. 1989;339:625-626. Bierer BE, Proc Natl Acad Sci . 1990;87:9231-9235.

Sirolimus Inhibits Angiogenesis ,[object Object],[object Object],[object Object],[object Object],Guba et al. Nature Med. 2002;8:128-135

Sirolimus: Anti-Angiogenic Activity in Mouse Model Guba et al. Nature Med. 2002;8:128-135

Pharmacokinetics Sirolimus RAPAMUNE ®

mTORi - CNI sparing regime ,[object Object],[object Object]

Stallone et al 2003 ,[object Object],[object Object],[object Object],[object Object],[object Object],Stallone G: Early withdrawal of cyclosporine A improves 1-year kidney graft structure and function in sirolimus-treated patients. Transplantation 2003 Reduce the impact of CNI by sirolimus

Stallone et al 2003 ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],Stallone G: Early withdrawal of cyclosporine A improves 1-year kidney graft structure and function in sirolimus-treated patients. Transplantation 2003 Reduce the impact of CNI by sirolimus

Gonwa et al 2002 ,[object Object],[object Object],[object Object],[object Object],[object Object],Gonwa GA; for the Sirolimus Renal Function Study Group: Improved renal function in sirolimus-treated renal transplant patients after early cyclosporine elimination. Transplantation 2002 Reduce the impact of CNI by sirolimus

Gonwa et al 2002 ,[object Object],[object Object],[object Object],[object Object],Gonwa GA; for the Sirolimus Renal Function Study Group: Improved renal function in sirolimus-treated renal transplant patients after early cyclosporine elimination. Transplantation 2002 Reduce the impact of CNI by sirolimus

Oberbauer et al 2003 ,[object Object],[object Object],[object Object],[object Object],[object Object],Reduce the impact of CNI by sirolimus Oberbauer R; for the Rapamune Maintenance Regimen Study Group: Long-term improvement in renal function with sirolimus after early cyclosporine withdrawal in renal transplant recipients: 2-year results of the Rapamune Maintenance Regimen Study. Transplantation 2003

Oberbauer et al 2003 ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],Reduce the impact of CNI by sirolimus Oberbauer R; for the Rapamune Maintenance Regimen Study Group: Long-term improvement in renal function with sirolimus after early cyclosporine withdrawal in renal transplant recipients: 2-year results of the Rapamune Maintenance Regimen Study. Transplantation 2003

Kreis et al 2004 ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],Reduce the impact of CNI by sirolimus Kreis H, Oberbauer R; for the Rapamune Maintenance Regimen Trial: Long-term benefits with sirolimus-based therapy after early cyclosporine withdrawal. J Am Soc Nephrol 2004

Baboolal et al 2004 ,[object Object],[object Object],[object Object],Reduce the impact of CNI by sirolimus Baboolal K: A phase III prospective, randomized study to evaluate concentration-controlled sirolimus (rapamune) with cyclosporine dose minimization or elimination at six months in de novo renal allograft recipients. Transplantation 75: 1404–1408, 2003

Mulay et al 2006 ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],Reduce the impact of CNI by sirolimus Conversion from Calcineurin Inhibitors to Sirolimus for Chronic Allograft Dysfunction: A Systemic Review of the Evidence Muray et al. Transplantation. 82(9):1153-1162, November 15, 2006.

Change from baseline in creatinine clearance after conversion to sirolimus. (A) Randomized controlled trials. (B) Nonrandomized studies. CI, confidence interval; MD, mean difference in change in creatinine clearance in ml/min from baseline between conversion and control arm; MC, mean change in creatinine clearance in mL/min from baseline. Mulay e tal . Transplantation. 82(9):1153-1162, November 15, 2006.

Mulay et al 2006 ,[object Object],[object Object],[object Object],Reduce the impact of CNI by sirolimus Muray et al. Transplantation. 82(9):1153-1162, November 15, 2006. Conversion from Calcineurin Inhibitors to Sirolimus for Chronic Allograft Dysfunction: A Systemic Review of the Evidence

Flechner et al 2007 ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],Reduce the impact of CNI by sirolimus Flechner et al. Transplantation:Volume 83(7)15 April 2007: 883-892 Kidney Transplantation With Sirolimus and Mycophenolate Mofetil-Based Immunosuppression: 5-Year Results of a Randomized Prospective Trial Compared to Calcineurin Inhibitor Drugs

Flechner et al 2007 ,[object Object],[object Object],[object Object],[object Object],[object Object],Reduce the impact of CNI by sirolimus Flechner et al. Transplantation:Volume 83(7)15 April 2007: 883-892 Kidney Transplantation With Sirolimus and Mycophenolate Mofetil-Based Immunosuppression: 5-Year Results of a Randomized Prospective Trial Compared to Calcineurin Inhibitor Drugs

Flechner et al 2007 ,[object Object],[object Object],Reduce the impact of CNI by sirolimus Flechner et al. Transplantation:Volume 83(7)15 April 2007: 883-892 Kidney Transplantation With Sirolimus and Mycophenolate Mofetil-Based Immunosuppression: 5-Year Results of a Randomized Prospective Trial Compared to Calcineurin Inhibitor Drugs

Delayed graft function ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],Lieberthal W et al: Role of cell-cycle arrest and apoptosis of tubular cells. Am J Physiol Renal Physiol 2001 Smith KD et: Delayed graft function and cast nephropathy associated with tacrolimus plus rapamycin use. J Am Soc Nephrol 2003 McTaggart RA et al: Sirolimus prolongs recovery from delayed graft function after cadaveric renal transplantation. Am J Transplant 2003

Delayed graft function ,[object Object],[object Object],[object Object],Stallone G et al: Addition of sirolimus to cyclosporine delays the recovery from delayed graft function but does not affect 1-year graft function. J Am Soc Nephrol 2004

Proteinuria ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],Perlman A et al: Clinically significant proteinuria following the administration of sirolimus to renal transplant recipients. J Am Soc Nephrol 2003 Hadaya K et al: Conversion to sirolimus after renal transplantation: High failure rate due to nephrotic proteinuria and other adverse events. J Am Soc Nephrol 2003

Other side effects ,[object Object],[object Object],[object Object],[object Object],[object Object],Valente JF et al: Comparison of sirolimus vs. mycophenolate mofetil on surgical complications and wound healing in adult kidney transplantation. Am J Transplant 2003 Flechner SM et al: The impact of sirolimus, mycophenolate mofetil, cyclosporine, azathioprine, and steroids on wound healing in 513 kidney-transplant recipients. Transplantation 2003

Other side effects ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],Fritsche L et al. Am J Transplant 2004 Haydar AA et al. Am J Transplant 2004 Paramesh AS et al. Transplantation 2004

Everolimus ,[object Object],[object Object],[object Object],[object Object],[object Object]

Sirolimus

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Sirolimus