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Pharmacology of mammalian (mechanistic) target of rapamycin (mTOR) inhibitors

Karen Hardinger, PharmD, BCPS
Daniel C Brennan, MD, FACP
Section Editor
Barbara Murphy, MB, BAO, BCh, FRCPI
Deputy Editor
Albert Q Lam, MD


There are two commercially available mammalian (mechanistic) target of rapamycin (mTOR) inhibitors Food and Drug Administration (FDA) approved in the United States: sirolimus and everolimus. Sirolimus (Rapamune, rapamycin) is a macrocyclic triene antibiotic that is produced by fermentation of Streptomyces hygroscopicus. Sirolimus was discovered from a soil sample collected in Rapa Nui, which is also known as Easter Island [1]. Although it was originally developed as an antifungal agent, it was later found to have immunosuppressive and antiproliferative properties that may be useful to treat or prevent proliferative diseases such as tuberous sclerosis, psoriasis, and malignancy. In April 2010, everolimus (Zortress), an analog of sirolimus and macrolide immunosuppressive agent, was approved by the FDA.

The pharmacology of the mTOR inhibitors and their use and efficacy in renal transplant recipients will be reviewed here. A discussion of immunosuppressive therapy in renal transplant recipients is presented separately. (See "Maintenance immunosuppressive therapy in renal transplantation in adults".)


Following entry into the cytoplasm, sirolimus and everolimus bind to the FK binding protein and presumably modulate the activity of the mammalian (mechanistic) target of rapamycin (mTOR) [2]. The mTOR inhibits interleukin-2 (IL-2)-mediated signal transduction, resulting in cell-cycle arrest in the G1-S phase [2,3]. Sirolimus and everolimus block the response of T- and B-cell activation by cytokines, which prevents cell-cycle progression and proliferation; in contrast, tacrolimus and cyclosporine inhibit the production of cytokines [4].

Sirolimus also appears to inhibit proliferation of smooth muscle cells [5], and, since there is activation of the sirolimus target in tuberous sclerosis lesions, may dampen the growth of angiomyolipomas with tuberous sclerosis [6]. Sirolimus may also have antimalignancy potential [7]. In March 2009, everolimus (Afinitor) received approval for treatment of advanced renal cell carcinoma. (See "Development of malignancy following solid organ transplantation".)



Peak concentration — The time to peak concentration of sirolimus and everolimus is one to two hours [3].

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Literature review current through: Nov 2017. | This topic last updated: Jul 27, 2016.
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  1. Sehgal SN, Baker H, Vézina C. Rapamycin (AY-22,989), a new antifungal antibiotic. II. Fermentation, isolation and characterization. J Antibiot (Tokyo) 1975; 28:727.
  2. Hardinger KL, Koch MJ, Brennan DC. Current and future immunosuppressive strategies in renal transplantation. Pharmacotherapy 2004; 24:1159.
  3. Product Information: Rapamune (sirolimus) Oral Solution and Tablets. Philadelphia, PA: Wyeth Laboratories, Division of Wyeth-Ayerst Pharmaceuticals Inc; January 2006.
  4. Kelly PA, Gruber SA, Behbod F, Kahan BD. Sirolimus, a new, potent immunosuppressive agent. Pharmacotherapy 1997; 17:1148.
  5. Cao W, Mohacsi P, Shorthouse R, et al. Effects of rapamycin on growth factor-stimulated vascular smooth muscle cell DNA synthesis. Inhibition of basic fibroblast growth factor and platelet-derived growth factor action and antagonism of rapamycin by FK506. Transplantation 1995; 59:390.
  6. El-Hashemite N, Zhang H, Henske EP, Kwiatkowski DJ. Mutation in TSC2 and activation of mammalian target of rapamycin signalling pathway in renal angiomyolipoma. Lancet 2003; 361:1348.
  7. Euvrard S, Morelon E, Rostaing L, et al. Sirolimus and secondary skin-cancer prevention in kidney transplantation. N Engl J Med 2012; 367:329.
  8. Zimmerman JJ, Kahan BD. Pharmacokinetics of sirolimus in stable renal transplant patients after multiple oral dose administration. J Clin Pharmacol 1997; 37:405.
  9. Product Information: Zortress (everolimus) Tablets. East Hanover, NJ: Novartis Pharmaceutical Corporation; April 2010.
  10. Kahan BD, Napoli KL. Role of therapeutic drug monitoring of rapamycin. Transplant Proc 1998; 30:2189.
  11. Ferron GM, Mishina EV, Zimmerman JJ, Jusko WJ. Population pharmacokinetics of sirolimus in kidney transplant patients. Clin Pharmacol Ther 1997; 61:416.
  12. Yatscoff R, LeGatt D, Keenan R, Chackowsky P. Blood distribution of rapamycin. Transplantation 1993; 56:1202.
  13. Briffa N, Morris RE. New immunosuppressive regimens in lung transplantation. Eur Respir J 1997; 10:2630.
  14. Yatscoff RW, Wang P, Chan K, et al. Rapamycin: distribution, pharmacokinetics, and therapeutic range investigations. Ther Drug Monit 1995; 17:666.
  15. Kahan BD. Efficacy of sirolimus compared with azathioprine for reduction of acute renal allograft rejection: a randomised multicentre study. The Rapamune US Study Group. Lancet 2000; 356:194.
  16. MacDonald AS, RAPAMUNE Global Study Group. A worldwide, phase III, randomized, controlled, safety and efficacy study of a sirolimus/cyclosporine regimen for prevention of acute rejection in recipients of primary mismatched renal allografts. Transplantation 2001; 71:271.
  17. Kahan BD, Napoli KL, Kelly PA, et al. Therapeutic drug monitoring of sirolimus: correlations with efficacy and toxicity. Clin Transplant 2000; 14:97.
  18. Groth CG, Bäckman L, Morales JM, et al. Sirolimus (rapamycin)-based therapy in human renal transplantation: similar efficacy and different toxicity compared with cyclosporine. Sirolimus European Renal Transplant Study Group. Transplantation 1999; 67:1036.
  19. Kreis H, Cisterne JM, Land W, et al. Sirolimus in association with mycophenolate mofetil induction for the prevention of acute graft rejection in renal allograft recipients. Transplantation 2000; 69:1252.
  20. Hartmann B, Schmid G, Graeb C, et al. Biochemical monitoring of mTOR inhibitor-based immunosuppression following kidney transplantation: a novel approach for tailored immunosuppressive therapy. Kidney Int 2005; 68:2593.
  21. Chan L, Hartmann E, Cibrik D, et al. Optimal everolimus concentration is associated with risk reduction for acute rejection in de novo renal transplant recipients. Transplantation 2010; 90:31.
  22. Dantal J, Berthoux F, Moal MC, et al. Efficacy and safety of de novo or early everolimus with low cyclosporine in deceased-donor kidney transplant recipients at specified risk of delayed graft function: 12-month results of a randomized, multicenter trial. Transpl Int 2010; 23:1084.
  23. Tedesco Silva H Jr, Cibrik D, Johnston T, et al. Everolimus plus reduced-exposure CsA versus mycophenolic acid plus standard-exposure CsA in renal-transplant recipients. Am J Transplant 2010; 10:1401.
  24. Vítko S, Margreiter R, Weimar W, et al. Three-year efficacy and safety results from a study of everolimus versus mycophenolate mofetil in de novo renal transplant patients. Am J Transplant 2005; 5:2521.
  25. Vítko S, Margreiter R, Weimar W, et al. Everolimus (Certican) 12-month safety and efficacy versus mycophenolate mofetil in de novo renal transplant recipients. Transplantation 2004; 78:1532.
  26. Knoll GA, Kokolo MB, Mallick R, et al. Effect of sirolimus on malignancy and survival after kidney transplantation: systematic review and meta-analysis of individual patient data. BMJ 2014; 349:g6679.
  27. Badve SV, Pascoe EM, Burke M, et al. Mammalian Target of Rapamycin Inhibitors and Clinical Outcomes in Adult Kidney Transplant Recipients. Clin J Am Soc Nephrol 2016; 11:1845.
  28. Augustine JJ, Knauss TC, Schulak JA, et al. Comparative effects of sirolimus and mycophenolate mofetil on erythropoiesis in kidney transplant patients. Am J Transplant 2004; 4:2001.
  29. Grinyó JM, Cruzado JM. Mycophenolate mofetil and sirolimus combination in renal transplantation. Am J Transplant 2006; 6:1991.
  30. Murgia MG, Jordan S, Kahan BD. The side effect profile of sirolimus: a phase I study in quiescent cyclosporine-prednisone-treated renal transplant patients. Kidney Int 1996; 49:209.
  31. Groth CG, Brattström C, Claesson K, Bäckman L. New trails in transplantation: how to exploit the potential of sirolimus in clinical transplantation. Transplant Proc 1998; 30:4064.
  32. Langer RM, Van Buren CT, Katz SM, Kahan BD. De novo hemolytic uremic syndrome after kidney transplantation in patients treated with cyclosporine a sirolimus combination. Transplant Proc 2001; 33:3236.
  33. Fortin MC, Raymond MA, Madore F, et al. Increased risk of thrombotic microangiopathy in patients receiving a cyclosporin-sirolimus combination. Am J Transplant 2004; 4:946.
  34. Crew RJ, Radhakrishnan J, Cohen DJ, et al. De novo thrombotic microangiopathy following treatment with sirolimus: report of two cases. Nephrol Dial Transplant 2005; 20:203.
  35. Kraemer FB, Takeda D, Natu V, Sztalryd C. Insulin regulates lipoprotein lipase activity in rat adipose cells via wortmannin- and rapamycin-sensitive pathways. Metabolism 1998; 47:555.
  36. Brattström C, Wilczek HE, Tydén G, et al. Hypertriglyceridemia in renal transplant recipients treated with sirolimus. Transplant Proc 1998; 30:3950.
  37. Kasiske BL, de Mattos A, Flechner SM, et al. Mammalian target of rapamycin inhibitor dyslipidemia in kidney transplant recipients. Am J Transplant 2008; 8:1384.
  38. van Gelder T, ter Meulen CG, Hené R, et al. Oral ulcers in kidney transplant recipients treated with sirolimus and mycophenolate mofetil. Transplantation 2003; 75:788.
  39. Smith MP, Newstead CG, Ahmad N, et al. Poor tolerance of sirolimus in a steroid avoidance regimen for renal transplantation. Transplantation 2008; 85:636.
  40. Morelon E, Stern M, Kreis H. Interstitial pneumonitis associated with sirolimus therapy in renal-transplant recipients. N Engl J Med 2000; 343:225.
  41. Pham PT, Pham PC, Danovitch GM, et al. Sirolimus-associated pulmonary toxicity. Transplantation 2004; 77:1215.
  42. Champion L, Stern M, Israël-Biet D, et al. Brief communication: sirolimus-associated pneumonitis: 24 cases in renal transplant recipients. Ann Intern Med 2006; 144:505.
  43. Weiner SM, Sellin L, Vonend O, et al. Pneumonitis associated with sirolimus: clinical characteristics, risk factors and outcome--a single-centre experience and review of the literature. Nephrol Dial Transplant 2007; 22:3631.
  44. Sabbatini M, Sansone G, Uccello F, et al. Acute effects of rapamycin on glomerular dynamics: a micropuncture study in the rat. Transplantation 2000; 69:1946.
  45. Andoh TF, Lindsley J, Franceschini N, Bennett WM. Synergistic effects of cyclosporine and rapamycin in a chronic nephrotoxicity model. Transplantation 1996; 62:311.
  46. Shihab FS, Bennett WM, Yi H, et al. Sirolimus increases transforming growth factor-beta1 expression and potentiates chronic cyclosporine nephrotoxicity. Kidney Int 2004; 65:1262.
  47. Saunders RN, Bicknell GR, Nicholson ML. The impact of cyclosporine dose reduction with or without the addition of rapamycin on functional, molecular, and histological markers of chronic allograft nephropathy. Transplantation 2003; 75:772.
  48. Gallon L, Perico N, Dimitrov BD, et al. Long-term renal allograft function on a tacrolimus-based, pred-free maintenance immunosuppression comparing sirolimus vs. MMF. Am J Transplant 2006; 6:1617.
  49. Mendez R, Gonwa T, Yang HC, et al. A prospective, randomized trial of tacrolimus in combination with sirolimus or mycophenolate mofetil in kidney transplantation: results at 1 year. Transplantation 2005; 80:303.
  50. Kobashigawa JA, Miller LW, Russell SD, et al. Tacrolimus with mycophenolate mofetil (MMF) or sirolimus vs. cyclosporine with MMF in cardiac transplant patients: 1-year report. Am J Transplant 2006; 6:1377.
  51. Kaplan B, Kirk AD. Tacrolimus and sirolimus: when bad things happen to good drugs. Am J Transplant 2006; 6:1501.
  52. McTaggart RA, Gottlieb D, Brooks J, et al. Sirolimus prolongs recovery from delayed graft function after cadaveric renal transplantation. Am J Transplant 2003; 3:416.
  53. Stallone G, Di Paolo S, Schena A, 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; 15:228.
  54. Smith KD, Wrenshall LE, Nicosia RF, et al. Delayed graft function and cast nephropathy associated with tacrolimus plus rapamycin use. J Am Soc Nephrol 2003; 14:1037.
  55. Dittrich E, Schmaldienst S, Soleiman A, et al. Rapamycin-associated post-transplantation glomerulonephritis and its remission after reintroduction of calcineurin-inhibitor therapy. Transpl Int 2004; 17:215.
  56. Butani L. Investigation of pediatric renal transplant recipients with heavy proteinuria after sirolimus rescue. Transplantation 2004; 78:1362.
  57. Izzedine H, Brocheriou I, Frances C. Post-transplantation proteinuria and sirolimus. N Engl J Med 2005; 353:2088.
  58. Senior PA, Paty BW, Cockfield SM, et al. Proteinuria developing after clinical islet transplantation resolves with sirolimus withdrawal and increased tacrolimus dosing. Am J Transplant 2005; 5:2318.
  59. Letavernier E, Pe'raldi MN, Pariente A, et al. Proteinuria following a switch from calcineurin inhibitors to sirolimus. Transplantation 2005; 80:1198.
  60. Sennesael JJ, Bosmans JL, Bogers JP, et al. Conversion from cyclosporine to sirolimus in stable renal transplant recipients. Transplantation 2005; 80:1578.
  61. Morelon E, Kreis H. Sirolimus therapy without calcineurin inhibitors: Necker Hospital 8-year experience. Transplant Proc 2003; 35:52S.
  62. Horita Y, Miyazaki M, Koji T, et al. Expression of vascular endothelial growth factor and its receptors in rats with protein-overload nephrosis. Nephrol Dial Transplant 1998; 13:2519.
  63. Laurinavicius A, Hurwitz S, Rennke HG. Collapsing glomerulopathy in HIV and non-HIV patients: a clinicopathological and follow-up study. Kidney Int 1999; 56:2203.
  64. Stephany BR, Augustine JJ, Krishnamurthi V, et al. Differences in proteinuria and graft function in de novo sirolimus-based vs. calcineurin inhibitor-based immunosuppression in live donor kidney transplantation. Transplantation 2006; 82:368.
  65. Letavernier E, Bruneval P, Mandet C, et al. High sirolimus levels may induce focal segmental glomerulosclerosis de novo. Clin J Am Soc Nephrol 2007; 2:326.
  66. Diekmann F, Gutiérrez-Dalmau A, López S, et al. Influence of sirolimus on proteinuria in de novo kidney transplantation with expanded criteria donors: comparison of two CNI-free protocols. Nephrol Dial Transplant 2007; 22:2316.
  67. Aliabadi AZ, Pohanka E, Seebacher G, et al. Development of proteinuria after switch to sirolimus-based immunosuppression in long-term cardiac transplant patients. Am J Transplant 2008; 8:854.
  68. Schena FP, Pascoe MD, Alberu J, et al. Conversion from calcineurin inhibitors to sirolimus maintenance therapy in renal allograft recipients: 24-month efficacy and safety results from the CONVERT trial. Transplantation 2009; 87:233.
  69. Straathof-Galema L, Wetzels JF, Dijkman HB, et al. Sirolimus-associated heavy proteinuria in a renal transplant recipient: evidence for a tubular mechanism. Am J Transplant 2006; 6:429.
  70. Pelletier R, Nadasdy T, Nadasdy G, et al. Acute renal failure following kidney transplantation associated with myoglobinuria in patients treated with rapamycin. Transplantation 2006; 82:645.
  71. Nee R, Hurst FP, Dharnidharka VR, et al. Racial variation in the development of posttransplant lymphoproliferative disorders after renal transplantation. Transplantation 2011; 92:190.
  72. EBPG Expert Group on Renal Transplantation. European best practice guidelines for renal transplantation. Section IV: Long-term management of the transplant recipient. IV.10. Pregnancy in renal transplant recipients. Nephrol Dial Transplant 2002; 17 Suppl 4:50.
  73. Zuber J, Anglicheau D, Elie C, et al. Sirolimus may reduce fertility in male renal transplant recipients. Am J Transplant 2008; 8:1471.
  74. Hardinger KL, Cornelius LA, Trulock EP 3rd, Brennan DC. Sirolimus-induced leukocytoclastic vasculitis. Transplantation 2002; 74:739.
  75. Pasqualotto AC, Bianco PD, Sukiennik TC, et al. Sirolimus-induced leukocytoclastic vasculitis: the second case reported. Am J Transplant 2004; 4:1549.
  76. Stallone G, Infante B, Di Paolo S, et al. Sirolimus and angiotensin-converting enzyme inhibitors together induce tongue oedema in renal transplant recipients. Nephrol Dial Transplant 2004; 19:2906.
  77. Duerr M, Glander P, Diekmann F, et al. Increased incidence of angioedema with ACE inhibitors in combination with mTOR inhibitors in kidney transplant recipients. Clin J Am Soc Nephrol 2010; 5:703.
  78. Mahé E, Morelon E, Lechaton S, et al. Cutaneous adverse events in renal transplant recipients receiving sirolimus-based therapy. Transplantation 2005; 79:476.
  79. Desai N, Heenan S, Mortimer PS. Sirolimus-associated lymphoedema: eight new cases and a proposed mechanism. Br J Dermatol 2009; 160:1322.
  80. Steele GH, Adamkovic AB, Demopoulos LA, et al. Pericardial effusion coincident with sirolimus therapy: a review of Wyeth's safety database. Transplantation 2008; 85:645.
  81. Kaplan B, Meier-Kriesche HU, Napoli KL, Kahan BD. The effects of relative timing of sirolimus and cyclosporine microemulsion formulation coadministration on the pharmacokinetics of each agent. Clin Pharmacol Ther 1998; 63:48.
  82. Chen H, Qi S, Xu D, et al. FK 506 and rapamycin in combination are not antagonistic but produce extended small bowel graft survival in the mouse. Transplant Proc 1998; 30:1039.
  83. McAlister VC, Mahalati K, Peltekian KM, et al. A clinical pharmacokinetic study of tacrolimus and sirolimus combination immunosuppression comparing simultaneous to separated administration. Ther Drug Monit 2002; 24:346.
  84. Holt DW, Ostraat O, Grinyo JM, et al. MMF may be given at lower doses when used in association with sirolimus in renal transplant recipients (abstract). Am J Transplant 2001; 1(Suppl 1):247.
  85. Hong JC, Kahan BD. Sirolimus rescue therapy for refractory rejection in renal transplantation. Transplantation 2001; 71:1579.
  86. Ghassemieh B, Ahya VN, Baz MA, et al. Decreased incidence of cytomegalovirus infection with sirolimus in a post hoc randomized, multicenter study in lung transplantation. J Heart Lung Transplant 2013; 32:701.
  87. Andrassy J, Hoffmann VS, Rentsch M, et al. Is cytomegalovirus prophylaxis dispensable in patients receiving an mTOR inhibitor-based immunosuppression? a systematic review and meta-analysis. Transplantation 2012; 94:1208.
  88. Nashan B, Gaston R, Emery V, et al. Review of cytomegalovirus infection findings with mammalian target of rapamycin inhibitor-based immunosuppressive therapy in de novo renal transplant recipients. Transplantation 2012; 93:1075.
  89. Swanson SJ, Hale DA, Mannon RB, et al. Kidney transplantation with rabbit antithymocyte globulin induction and sirolimus monotherapy. Lancet 2002; 360:1662.
  90. Lim WH, Eris J, Kanellis J, et al. A systematic review of conversion from calcineurin inhibitor to mammalian target of rapamycin inhibitors for maintenance immunosuppression in kidney transplant recipients. Am J Transplant 2014; 14:2106.
  91. Yanik EL, Siddiqui K, Engels EA. Sirolimus effects on cancer incidence after kidney transplantation: a meta-analysis. Cancer Med 2015; 4:1448.