DOI QR코드

DOI QR Code

Real-World Efficacy and Safety of Everolimus with Low Dose Tacrolimus in Liver Transplantation Recipients

실제 임상현장에서의 간이식 환자 대상 Everolimus와 저용량 Tacrolimus 병용요법의 유효성 및 안전성 평가

  • Jang, Seoyoun (Department of Pharmacy, Seoul National University Bundang Hospital) ;
  • Kim, Boram (Department of Pharmacy, Seoul National University Bundang Hospital) ;
  • Jeon, Sujeong (Department of Pharmacy, Seoul National University Bundang Hospital) ;
  • Choi, Kyung Suk (Department of Pharmacy, Seoul National University Bundang Hospital) ;
  • Lee, Eunsook (Department of Pharmacy, Seoul National University Bundang Hospital) ;
  • Lee, Ju-Yeun (College of pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University) ;
  • Lee, Euni (College of pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University) ;
  • Han, Ho-Seong (Department of Surgery, Seoul National University Bundang Hospital) ;
  • Cho, Jai Young (Department of Surgery, Seoul National University Bundang Hospital)
  • 장서윤 (분당서울대학교병원 약제부) ;
  • 김보람 (분당서울대학교병원 약제부) ;
  • 전수정 (분당서울대학교병원 약제부) ;
  • 최경숙 (분당서울대학교병원 약제부) ;
  • 이은숙 (분당서울대학교병원 약제부) ;
  • 이주연 (서울대학교 약학대학) ;
  • 김은경 (서울대학교 약학대학) ;
  • 한호성 (분당서울대학교병원 외과) ;
  • 조재영 (분당서울대학교병원 외과)
  • Received : 2020.11.23
  • Accepted : 2021.02.23
  • Published : 2021.03.31

Abstract

Background: Post-transplant immunosuppression with calcineurin inhibitors (CNIs) is associated with kidney function impairment while mammalian target of rapamycin (mTOR) inhibitors, such as everolimus, can be used for its renal-sparing effects. In this study, we compared the efficacy and safety of everolimus with low dose tacrolimus (EVR+Low TAC) and conventional dose tacrolimus (TAC) in liver transplantation recipients. Methods: Medical records of recipients who received liver transplantation at Seoul National University Bundang Hospital from January 1st 2009 to December 31st 2018 were retrospectively reviewed. Cohort entry date was defined as the day everolimus was initiated and tacrolimus dosage was reduced. All patients were followed up for 1 year. Indicator of efficacy was the incidence of rejection and safety was evaluated by incidence of drug adverse events including renal function. Results: Among 118 patients, there were 40 patients (33.9%) in EVR+Low TAC group. Incidence of rejection, including both biopsy proven acute rejection and clinical rejection, was similar in two groups [7.5% (n=3) vs. 6.4% (n=5), p=1.000]. Renal dysfunction was less frequent in EVR+Low TAC [17.5% (n=7) vs. 35.9% (n=28), p=0.038]. However, incidence rates of dyslipidemia, oral ulcer were more frequent in EVR+Low TAC [45.0% (n=18) vs. 21.8% (n=17), p=0.009; 15.0% (n=6) vs. 1.3% (n=1), p=0.006]. Conclusions: In terms of prevention of rejection, EVR+Low TAC was as effective as TAC and had renal-sparing effect but was associated with increased risk of dyslipidemia and oral ulcer. This study demonstrates that EVR+Low TAC could be an alternative to liver transplant recipients with nephrotoxicity after administration of conventional dose tacrolimus.

Keywords

References

  1. Oh CK, Huh KH, Ha J, Kim YH, Kim YL, Kim YS. Safety and efficacy of the early introduction of everolimus with reduced-exposure cyclosporine a in de novo kidney recipients. Transplantation 2015;99(1):180-6. https://doi.org/10.1097/TP.0000000000000225
  2. Jeng LB, Lee SG, Soin AS, et al. Efficacy and safety of everolimus with reduced tacrolimus in living-donor liver transplant recipients: 12-month results of a randomized multicenter study. Am J Transplant 2018;18(6):1435-46. https://doi.org/10.1111/ajt.14623
  3. Lin M, Mittal S, Sahebjam F, Rana A, Sood GK. Everolimus with early withdrawal or reduced-dose calcineurin inhibitors improves renal function in liver transplant recipients: A systematic review and meta-analysis. Clin Transplant 2017;31(2).
  4. Saliba F, Duvoux C, Gugenheim J, et al. Efficacy and safety of everolimus and mycophenolic acid with early tacrolimus withdrawal after liver transplantation: A multicenter randomized trial. Am J Transplant 2017;17(7):1843-52. https://doi.org/10.1111/ajt.14212
  5. Cholongitas E, Goulis I, Theocharidou E, et al. Everolimus with or without mycophenolate mofetil in a liver transplantation setting: A single-center experience. Ann Gastroenterol 2018;31(5):613-20.
  6. Morard I, Mentha G, Spahr L, et al. Long-term renal function after liver transplantation is related to calcineurin inhibitors blood levels. Clin Transplant 2006;20(1):96-101. https://doi.org/10.1111/j.1399-0012.2005.00447.x
  7. Herden U, Galante A, Fischer L, et al. Early initiation of everolimus after liver transplantation: A single-center experience. Ann Transplant 2016;21:77-85. https://doi.org/10.12659/AOT.895800
  8. Flechner SM, Kobashigawa J, Klintmalm G. Calcineurin inhibitor-sparing regimens in solid organ transplantation: Focus on improving renal function and nephrotoxicity. Clin Transplant 2008;22(1):1-15. https://doi.org/10.1111/j.1399-0012.2007.00739.x
  9. Kim MS, Kim SI, Kim YS. Clinical application of mammalian target of rapamycin inhibitor in kidney transplantation. J Korean Soc Transplant 2008;22(2):169-76.
  10. Saliba F, De Simone P, Nevens F, et al. Renal function at two years in liver transplant patients receiving everolimus: Results of a randomized, multicenter study. Am J Transplant 2013;13(7):1734-45. https://doi.org/10.1111/ajt.12280
  11. Kovarik JM, Tedesco H, Pascual J, et al. Everolimus therapeutic concentration range defined from a prospective trial with reduced-exposure cyclosporine in de novo kidney transplantation. Ther Drug Monit 2004;26(5):499-505. https://doi.org/10.1097/00007691-200410000-00007
  12. Lorber MI, Mulgaonkar S, Butt KM, et al. Everolimus versus mycophenolate mofetil in the prevention of rejection in de novo renal transplant recipients: A 3-year randomized, multicenter, phase iii study. Transplantation 2005;80(2):244-52. https://doi.org/10.1097/01.TP.0000164352.65613.24
  13. Tedesco-Silva H, Jr., Vitko S, Pascual J, et al. 12-month safety and efficacy of everolimus with reduced exposure cyclosporine in de novo renal transplant recipients. Transpl Int 2007;20(1):27-36. https://doi.org/10.1111/j.1432-2277.2006.00414.x
  14. Vitko 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(10):1532-40. https://doi.org/10.1097/01.TP.0000141094.34903.54
  15. Vitko S, Tedesco H, Eris J, et al. Everolimus with optimized cyclosporine dosing in renal transplant recipients: 6-month safety and efficacy results of two randomized studies. Am J Transplant 2004;4(4):626-35. https://doi.org/10.1111/j.1600-6143.2004.00389.x
  16. Ministry of Food and Drug Safety. Certican 0.5mg(everolimus). Available from https://nedrug.mfds.go.kr/pbp/CCBBB01/getItem Detail?itemSeq=200603863. Accessed February 10, 2021
  17. De Simone P, Nevens F, De Carlis L, et al. Everolimus with reduced tacrolimus improves renal function in de novo liver transplant recipients: A randomized controlled trial. Am J Transplant 2012; 12(11):3008-20. https://doi.org/10.1111/j.1600-6143.2012.04212.x
  18. Lee SY, Kim S, Min MS, Kim JM, Lee YM. Everolimus-based therapy in liver transplant recipients: Its efficacy and safety in a real practice. J. Kor. Soc. of Health-syst. Pharm 2018;35(2):135-42. https://doi.org/10.32429/jkshp.2018.35.2.001
  19. Ormonde DG, de Boer WB, Kierath A, et al. Banff schema for grading liver allograft rejection: Utility in clinical practice. Liver Transpl Surg 1999;5(4):261-8. https://doi.org/10.1002/lt.500050418
  20. Astellas. Prograf® 2021. Available from https://www.astellas.com/kr/ko/product/prograf. Accessed February 10, 2021.
  21. Fischer L, Klempnauer J, Beckebaum S, et al. A randomized, controlled study to assess the conversion from calcineurin-inhibitors to everolimus after liver transplantation--PROTECT. Am J Transplant 2012;12(7):1855-65. https://doi.org/10.1111/j.1600-6143.2012.04049.x
  22. Montalti R, Mimmo A, Rompianesi G, et al. Early use of mammalian target of rapamycin inhibitors is an independent risk factor for incisional hernia development after liver transplantation. Liver Transpl 2012;18(2):188-94. https://doi.org/10.1002/lt.22445
  23. Jeng LB, Thorat A, Hsieh YW, et al. Experience of using everolimus in the early stage of living donor liver transplantation. Transplant Proc 2014;46(3):744-8. https://doi.org/10.1016/j.transproceed.2013.11.068
  24. Fung J, Marcos A. Rapamycin: Friend, foe, or misunderstood? Liver Transpl 2003;9(5):469-72. https://doi.org/10.1053/jlts.2003.50101
  25. Porta C, Osanto S, Ravaud A, et al. Management of adverse events associated with the use of everolimus in patients with advanced renal cell carcinoma. Eur J Cancer 2011;47(9):1287-98. https://doi.org/10.1016/j.ejca.2011.02.014
  26. Kaplan B, Qazi Y, Wellen JR. Strategies for the management of adverse events associated with mtor inhibitors. Transplant Rev (Orlando) 2014;28(3):126-33. https://doi.org/10.1016/j.trre.2014.03.002
  27. Fraenkel M, Ketzinel-Gilad M, Ariav Y, et al. Mtor inhibition by rapamycin prevents beta-cell adaptation to hyperglycemia and exacerbates the metabolic state in type 2 diabetes. Diabetes 2008;57(4):945-57. https://doi.org/10.2337/db07-0922
  28. Houde VP, Brule S, Festuccia WT, et al. Chronic rapamycin treatment causes glucose intolerance and hyperlipidemia by upregulating hepatic gluconeogenesis and impairing lipid deposition in adipose tissue. Diabetes 2010;59(6):1338-48. https://doi.org/10.2337/db09-1324
  29. Engels EA, Pfeiffer RM, Fraumeni JF, Jr., et al. Spectrum of cancer risk among us solid organ transplant recipients. JAMA 2011;306(17):1891-901. https://doi.org/10.1001/jama.2011.1592
  30. Acuna SA, Fernandes KA, Daly C, et al. Cancer mortality among recipients of solid-organ transplantation in ontario, canada. JAMA Oncol 2016;2(4):463-9. https://doi.org/10.1001/jamaoncol.2015.5137
  31. Holdaas H, De Simone P, Zuckermann A. Everolimus and malignancy after solid organ transplantation: A clinical update. J Transplant 2016;2016:4369574.
  32. Guan TW, Lin YJ, Ou MY, Chen KB. Efficacy and safety of everolimus treatment on liver transplant recipients: A meta-analysis. Eur J Clin Invest 2019;49(12):e13179.
  33. Holdaas H, Potena L, Saliba F. mTor inhibitors and dyslipidemia in transplant recipients: A cause for concern? Transplant Rev (Orlando) 2015;29(2):93-102. https://doi.org/10.1016/j.trre.2014.08.003
  34. Pereira MJ, Palming J, Rizell M, et al. The immunosuppressive agents rapamycin, cyclosporin a and tacrolimus increase lipolysis, inhibit lipid storage and alter expression of genes involved in lipid metabolism in human adipose tissue. Mol Cell Endocrinol 2013;365(2):260-9. https://doi.org/10.1016/j.mce.2012.10.030