Sirolimus

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  • Sirolimus

    1. 1. Mamalian Target of Rapamycin inhibitor Sirolimus
    2. 2. Mamalian Target of Rapamycin inhibitor Sirolimus
    3. 3. Contents <ul><li>History </li></ul><ul><li>Mechanism of action </li></ul><ul><ul><li>mTOR </li></ul></ul><ul><ul><li>FKBP </li></ul></ul><ul><ul><li>Anti-proliferative </li></ul></ul><ul><ul><li>Effect on apoptosis </li></ul></ul><ul><li>Clinical usage - Reducing impact of CNI </li></ul><ul><ul><li>Stallone 2003 </li></ul></ul><ul><ul><li>Gonwa 2004 </li></ul></ul><ul><ul><li>Oberbauer 2003 </li></ul></ul><ul><ul><li>Kreis 2004 </li></ul></ul><ul><ul><li>Baboolal 2004 </li></ul></ul><ul><ul><li>Mulay et al 200 6 </li></ul></ul><ul><ul><li>Flechner et al 200 7 </li></ul></ul><ul><li>Side effects </li></ul><ul><ul><li>Delayed graft function </li></ul></ul><ul><ul><li>Proteinuria </li></ul></ul><ul><ul><li>Others </li></ul></ul><ul><li>Everolimus </li></ul>
    4. 4. 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
    5. 6. Pharmacology Pharmacokinetics Pharmacodynamics Sirolimus
    6. 7. Structure and mechanism of action Sirolimus
    7. 8. 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 <ul><li>Macrocyclic lactone </li></ul><ul><li>isolated from Streptomyces hygroscopicus </li></ul><ul><li>Molecular weight 914.2 </li></ul><ul><li>Binds to FKBP12 </li></ul>
    8. 10. Mechanism of action <ul><li>Cyclosporine Tacrolimus Sirolmus </li></ul><ul><li>Binding protein Cyclophilin FKBP12 FKBP12 </li></ul><ul><li>Effector protein Calcineurin Calcineurin mTOR </li></ul><ul><li>IL-2 message Inhibited Inhibited – </li></ul><ul><li>IL-2 response – – Inhibited </li></ul><ul><li>Cell-cycle effect G 0 -G 1 G 0 -G 1 G 1 -S </li></ul>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
    9. 15. 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
    10. 16. 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
    11. 17. FKBP <ul><li>FKBP - FK506 binding protein </li></ul><ul><li>FKBP12 - binding protein for the immunosuppressant molecule tacrolimus (originally designated FK506) </li></ul><ul><li>FBKP-tacrolimus complex </li></ul><ul><ul><li>inhibit a phosphatase called calcineurin which block the signal transduction in T-lymphocyte transduction pathway </li></ul></ul>
    12. 19. Mammalian target of rapamycin <ul><li>mTOR </li></ul><ul><ul><li>mammalian target of rapamycin </li></ul></ul><ul><ul><li>serine/threonine protein kinase </li></ul></ul><ul><ul><li>regulates cell growth, cell proliferation, cell motility, cell survival, protein synthesis, and transcription. </li></ul></ul>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.
    13. 20. mTOR has been shown to function as the catalytic subunit of two distinct molecular complexes in cells.
    14. 21. Sirolimus Demonstrates Anti-Proliferative Activity Against a Variety of Cell Types <ul><li>Dose-dependent anti-proliferative activity triggered by: </li></ul><ul><ul><li>Platelet derived growth factor (PDGF) </li></ul></ul><ul><ul><ul><li>Vascular smooth muscle cell chemotaxis </li></ul></ul></ul><ul><ul><li>Basic fibroblast growth factor (bFGF) </li></ul></ul><ul><ul><ul><li>Vascular smooth muscle cell mitogen </li></ul></ul></ul><ul><ul><li>Endothelial cell growth factor (ECGF) </li></ul></ul><ul><ul><ul><li>Endothelial cell proliferation </li></ul></ul></ul><ul><ul><li>Transforming Growth Factor Beta (TGF-  ) </li></ul></ul><ul><ul><ul><li>Stimulates vascular smooth muscle cell migration </li></ul></ul></ul><ul><ul><ul><li>Stimulates vascular smooth muscle cell deposition </li></ul></ul></ul>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.
    15. 22. Effect of Sirolimus on Apoptosis <ul><li>Preserve T-cell apoptosis </li></ul><ul><li>May be essential for long-term allograft survival </li></ul><ul><li>Postulated as critical to induction of tolerance </li></ul>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.
    16. 23. Animal studies
    17. 29. Sirolimus Inhibits Angiogenesis <ul><li>Shown to inhibit angiogenesis in an in vivo mouse model </li></ul><ul><li>Antiangiogenic effect related to: </li></ul><ul><ul><li>Decreased vascular endothelial growth factor (VEGF) </li></ul></ul><ul><ul><li>Inhibited response of vascular endothelial cells to stimulation by VEGF </li></ul></ul>Guba et al. Nature Med. 2002;8:128-135
    18. 30. Sirolimus: Anti-Angiogenic Activity in Mouse Model Guba et al. Nature Med. 2002;8:128-135
    19. 31. Sirolimus: Anti-Angiogenic Activity in Mouse Model Guba et al. Nature Med. 2002;8:128-135
    20. 32. Pharmacokinetics Sirolimus RAPAMUNE ®
    21. 39. mTORi - CNI sparing regime <ul><li>The drug itself is associated with little nephrotoxicity </li></ul><ul><li>Used in calcineurin inhibitor–sparing regimens </li></ul>
    22. 40. Stallone et al 2003 <ul><li>Randomized 40 patients (after three months of therapy with corticosteroids, cyclosporine, and sirolimus) to </li></ul><ul><ul><li>Continue the regimen </li></ul></ul><ul><ul><li>or </li></ul></ul><ul><ul><li>withdraw cyclosporine </li></ul></ul><ul><li>Endpoint: biopsy 12 mo after randomization </li></ul>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
    23. 41. Stallone et al 2003 <ul><li>Chronic allograft nephropathy was diagnosed in 55% of the 40 patients studied </li></ul><ul><ul><li>64% were in the CsA group </li></ul></ul><ul><ul><li>moderate to severe CAN in 90% of those patients </li></ul></ul><ul><li>CAN were less serious in sirolimus group </li></ul><ul><li>Elevations in serum creatinine: </li></ul><ul><ul><li>cyclosporine group (2.0 mg/dl) </li></ul></ul><ul><ul><li>sirolimus grouop (1.3 mg/dl) </li></ul></ul>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
    24. 42. Gonwa et al 2002 <ul><li>197 cadaveric renal transplant recipients, multicenter study </li></ul><ul><ul><li>randomized to </li></ul></ul><ul><ul><li>full-dose Neoral® plus fixed dose sirolimus (n = 97) </li></ul></ul><ul><ul><li>or </li></ul></ul><ul><ul><li>reduced dose Neoral® plus concentration-controlled sirolimus using trough levels of 10 to 20 ng/ml (n = 100). </li></ul></ul>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
    25. 43. Gonwa et al 2002 <ul><li>Twelve months after transplantation </li></ul><ul><ul><li>Creatinine were lower in the cyclosporine minimization arm of the study (1.38 mg/dl versus 1.82 mg/dl) </li></ul></ul><ul><ul><li>Biopsy-proven acute rejection was similar between groups staying on cyclosporine and those eliminating cyclosporine. </li></ul></ul><ul><ul><li>Graft survival rates in both groups were 96%. </li></ul></ul>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
    26. 44. Oberbauer et al 2003 <ul><li>Shortly after renal transplant, 525 patients received sirolimus, cyclosporine, and steroids. </li></ul><ul><ul><li>At 3 mo, 430 patients were randomly assigned to </li></ul></ul><ul><ul><li>remain on triple drug therapy (Srl + CsA + steroid) </li></ul></ul><ul><ul><li>or </li></ul></ul><ul><ul><li>cyclosporine withdrawn with an increase in the sirolimus (trough blood levels targeted to 20 to 30 ng/ml) </li></ul></ul>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
    27. 45. Oberbauer et al 2003 <ul><li>At two years </li></ul><ul><ul><li>serum creatinine level was significantly better in patients undergoing cyclosporine withdrawal </li></ul></ul><ul><ul><ul><li>128 mol/L (CsA withdrawal, Srl + Steroid) </li></ul></ul></ul><ul><ul><ul><li>versus </li></ul></ul></ul><ul><ul><ul><li>167 mol/L (Srl + CsA + Steroid) </li></ul></ul></ul><ul><ul><li>BP was also lower </li></ul></ul>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
    28. 46. Oberbauer et al 2003 <ul><li>Patient survival and graft survival showed no statistically significant differences </li></ul><ul><li>Acute rejection after randomization was </li></ul><ul><ul><li>9.8% in cyclosporine-withdrawn patients </li></ul></ul><ul><ul><li>versus </li></ul></ul><ul><ul><li>5.1% in patients remaining on cyclosporine </li></ul></ul>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
    29. 47. Kreis et al 2004 <ul><li>Same study of Oberbauer’s study, results at 36 mo </li></ul><ul><li>Improved graft survival tendency in cyclosporine-withdrawn patients </li></ul><ul><ul><li>91.2% </li></ul></ul><ul><ul><li>versus </li></ul></ul><ul><ul><li>85.1%, </li></ul></ul><ul><ul><li>despite more biopsy-proven rejections, 10.2% versus 5.6% </li></ul></ul>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
    30. 48. Baboolal et al 2004 <ul><li>Study examining cyclosporine elimination versus cyclosporine dose minimization </li></ul><ul><li>In patients randomized to elimination of cyclosporine, creatinine clearance was significantly higher with no significant increase in acute rejection episodes. </li></ul><ul><li>“ Cyclosporine minimization group versus the cyclosporine elimination group did not affect immunosuppressive efficacy” </li></ul>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
    31. 49. Mulay et al 2006 <ul><li>5 randomized trials (n=1,040 patients) and 25 nonrandomized studies (n=977 patients) </li></ul><ul><li>In randomized trials </li></ul><ul><ul><li>Conversion to sirolimus improved short-term creatinine clearance compared to control </li></ul></ul><ul><ul><li>28% patients discontinued </li></ul></ul><ul><li>In nonrandomized trials, conversion to sirolimus… </li></ul><ul><ul><li>improved renal function in 66% </li></ul></ul><ul><ul><li>increased cholesterol and TG </li></ul></ul><ul><ul><li>17% patients discontinued </li></ul></ul>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.
    32. 50. 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.
    33. 51. Mulay et al 2006 <ul><li>Conclusion </li></ul><ul><ul><li>Conversion in sirolimus associated with an improvement in short-term renal function. </li></ul></ul><ul><ul><li>Adequately powered randomized trials with longer follow-up of hard outcomes are needed. </li></ul></ul>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
    34. 52. Flechner et al 2007 <ul><li>Randomized prospective trial, 5-year outcomes </li></ul><ul><li>Designed to evaluate CNI-free immunosuppression on kidney transplant function </li></ul><ul><li>After Basiliximab induction, 61 patients randomized to </li></ul><ul><ul><li>Sirolimus (n=31) </li></ul></ul><ul><ul><li>or </li></ul></ul><ul><ul><li>Cyclosporine (n=30) </li></ul></ul><ul><li>Both arms receinced MMF and steroids </li></ul><ul><li>Sirolimus level controlled at 10-12 ng/mL for at least 6 mo </li></ul>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
    35. 53. Flechner et al 2007 <ul><li>After 5 years, SRL-MMF-steroids vs CsA-MMF-steroids: </li></ul><ul><li>Similar patient survival (87.1 vs 90%, p =0.681) </li></ul><ul><li>Similar acute rejection rates (12.9 vs 23.3%, p= 0.22) </li></ul><ul><li>Similar cholesterol (209 vs 294, p =0.973) </li></ul><ul><li>Similar Ur Protein/Creat ratios (0.398 vs 0.478, p=0.72 ) </li></ul>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
    36. 54. Flechner et al 2007 <ul><li>Sirolimus based CNI-free patients had longer death censored graft survival (96.4 vs 76.7% p =0.0265) </li></ul><ul><li>Higher MDRD GFR (66.7 vs 50.7ml/min, p =0.0075) </li></ul>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
    37. 55. Side effects
    38. 56. Delayed graft function <ul><li>Lieberthal et al 2001 </li></ul><ul><ul><li>Predicted DGF in an experimental studies of ischemic models in animals </li></ul></ul><ul><li>Smith et al 2003 </li></ul><ul><ul><li>Delayed graft function was more common in patients treated with sirolimus than without, 25% versus 8.9% </li></ul></ul><ul><li>McTaggart et al 2003 </li></ul><ul><ul><li>sirolimus are twice as likely to need prolonged dialysis as patients receiving other immunosuppressive regimens. </li></ul></ul>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
    39. 57. Delayed graft function <ul><li>Stallone et al 2004 </li></ul><ul><ul><li>Reported slow recovery from delayed graft function but showed that this did not worsen 1-yr graft function. </li></ul></ul><ul><ul><li>The long-term effects of DGF remain to be seen and are likely to be negative </li></ul></ul>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
    40. 58. Proteinuria <ul><li>Perlman et al 2003 </li></ul><ul><ul><li>Before sirolimus, proteinuria averaged 1.46 g/24 h, increased to 8.8 g/24 h within 3 to 4 wk after initiation of sirolimus. </li></ul></ul><ul><ul><li>All patients had reduction in proteinuria after sirolimus was withdrawn but in no patient did the proteinuria drop to baseline. </li></ul></ul><ul><li>Hadaya et al </li></ul><ul><ul><li>23 patients converted to sirolimus </li></ul></ul><ul><ul><li>incidence of increased proteinuria in nearly one third of patients </li></ul></ul>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
    41. 59. Other side effects <ul><li>Valente et al </li></ul><ul><ul><li>Greater incidence of lymphoceles, perinephric fluid collections, and poor wound healing </li></ul></ul><ul><li>Flechner et al </li></ul><ul><ul><li>No increase in wound complications since the introduction of MMF and sirolimus in their program. </li></ul></ul><ul><ul><li>They point to increased body weight of recipients as the primary factor associated with impaired wound healing. </li></ul></ul>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
    42. 60. Other side effects <ul><li>Fritshe 2004 </li></ul><ul><ul><li>Reduction in serum testosterone levels with increases in follicle stimulating hormone and luteinizing hormone </li></ul></ul><ul><li>Haydar 2004 </li></ul><ul><ul><li>Drug-induced pneumonitis (Haydar 2004) </li></ul></ul><ul><li>Paramesh 2004 </li></ul><ul><ul><li>Thrombotic microangiopathy (Paramesh 2004) </li></ul></ul>Fritsche L et al. Am J Transplant 2004 Haydar AA et al. Am J Transplant 2004 Paramesh AS et al. Transplantation 2004
    43. 61. Everolimus <ul><li>Similar side effects with sirolimus: </li></ul><ul><ul><li>hyperlipidemia, thrombocytopenia, leukopenia,and anemia </li></ul></ul><ul><ul><li>class effect. </li></ul></ul><ul><li>Shorter half-life than sirolimus </li></ul><ul><li>Similar biologic effects </li></ul>

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