Efficacy and safety of concentration-controlled everolimus with reduced-dose cyclosporine in Japanese de novo renal transplant patients: 12-month results

详细信息    查看全文

• 作者：Kota Takahashi (11)
  Kazuharu Uchida (12)
  Norio Yoshimura (13)
  Shiro Takahara (9)
  Satoshi Teraoka (10)
  Rie Teshima (11)
  Catherine Cornu-Artis (12)
  Eiji Kobayashi (13)
  
• 关键词：Everolimus ; Cyclosporine ; Renal transplantation ; Renal function ; Therapeutic drug monitoring
• 刊名：Transplantation Research
• 出版年：2013
• 出版时间：December 2013
• 年：2013
• 卷：2
• 期：1
• 全文大小：236KB
• 参考文献：1. The Japanese Society for Clinical Renal Transplantation: Annual progress report from the Japanese renal transplant registry: number of renal transplantations in 2008, part 2. / ISYOKU 2009, 44:548.
  2. Golshayan D, Pascual M: Minimization of calcineurin inhibitors to improve long-term outcomes in kidney transplantation. / Transpl Immunol 2008, 20:21. CrossRef
  3. Nankivell BJ, Borrows RJ, Fung CL, O鈥機onnell PJ, Allen RD, Chapman JR: The natural history of chronic allograft nephropathy. / N Engl J Med 2003, 349:2326. CrossRef
  4. Nankivell BJ, Borrows RJ, Fung CL, O鈥機onnell PJ, Chapman JR, Allen RD: Calcineurin inhibitor nephrotoxicity: longitudinal assessment by protocol histology. / Transplantation 2004, 78:557. CrossRef
  5. Schuler W, Sedrani R, Cottens S, H盲berlin B, Schulz M, Schuurman HJ, Zenke G, Zerwes HG, Schreier MH: SDZ RAD, a new rapamycin derivative: pharmacological properties in vitro and in vivo. / Transplantation 1997, 64:36. CrossRef
  6. Tedesco-Silva H Jr, Vitko S, Pascual J, Eris J, Magee JC, Whelchel J, Civati G, Campbell S, Alves-Filho G, Bourbigot B, Garcia VD, Leone J, Esmeraldo R, Rigotti P, Cambi V: Haas T; 2306 and 2307 Study Groups: 12-month safety and efficacy of everolimus with reduced exposure cyclosporine in de novo renal transplant recipients. / Transpl Int 2007, 20:27. CrossRef
  7. Lorber MI, Mulgaonkar S, Butt KM, Elkhammas E, Mendez R, Rajagopalan PR, Kahan B, Sollinger H, Li Y, Cretin N: Tedesco H; B251 Study Group: 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, 80:244. CrossRef
  8. Vitko S, Tedesco H, Eris J, Pascual J, Whelchel J, Magee JC, Campbell S, Civati G, Bourbigot B, Alves Filho G, Leone J, Garcia VD, Rigotti P, Esmeraldo R, Cambi V, Haas T, Jappe A, Bernhardt P, Geissler J, Cretin N: Everolimus with optimized cyclosporine dosing in renal transplant recipients: 6-month safety and efficacy results of two randomized studies. / Am J Transplant 2004, 4:626. CrossRef
  9. Vitko S, Margreiter R, Weimar W, Dantal J, Kuypers D, Winkler M, 脴yen O, Viljoen HG, Filiptsev P, Sadek S, Li Y, Cretin N, Budde K: RAD B201 Study Group: 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. CrossRef
  10. Nashan B, Curtis J, Ponticelli C, Mourad G, Jaffe J, Haas T: Everolimus and reduced-exposure cyclosporine in de novo renal-transplant recipients: a three-year phase II, randomized, multicenter, open-label study. / Transplantation 2004, 78:1332. CrossRef
  11. Chan L, Greenstein S, Hardy MA, Hartmann E, Bunnapradist S, Cibrik D, Shaw LM, Munir L, Ulbricht B, Cooper M: CRADUS09 Study Group: Multicenter, randomized study of the use of everolimus with tacrolimus after renal transplantation demonstrates its effectiveness. / Transplantation 2008, 85:821. CrossRef
  12. Tedesco-Silva H Jr, Cibrik D, Johnston T, Lackova E, Mange K, Panis C, Walker R, Wang Z, Zibari G, Kim YS: Everolimus plus reduced-exposure CsA versus mycophenolic acid plus standard-exposure CsA in renal-transplant recipients. / Am J Transplant 2010, 10:1401. CrossRef
  13. Dantal J, Francois Berthoux F, Moal M-C, Rostaing L, Legendre C, Genin R, Toupance O, Moulin B, Merville P, Rerolle JP, Bayle F, Westeel PF, Glotz D, Kossari N, Lefran莽ois N, Charpentier B, Qu茅r茅 S, Di Giambattista F, Cassuto E: RAD A2420 Study Group: 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. CrossRef
  14. Salvadori M, Scolari MP, Bertoni E, Citterio F, Rigotti P, Cossu M, Dal Canton A, Tisone G, Albertazzi A, Pisani F, Gubbiotti G, Piredda G, Busnach G, Sparacino V, Goepel V, Messa P, Berloco P, Montanaro D, Veroux P, Federico S, Bartezaghi M, Corbetta G, Ponticelli C: Everolimus with very low-exposure cyclosporine a in de novo kidney transplantation: a multicenter, randomized, controlled trial. / Transplantation 2009, 88:1194. CrossRef
  15. Vitko S, Margreiter R, Weimar W, Dantal J, Viljoen HG, Li Y, Jappe A, Cretin N: RAD B201 Study Group: Everolimus (Certican) 12-month safety and efficacy versus mycophenolate mofetil in de novo renal transplant recipients. / Transplantation 2004, 78:1532. CrossRef
  16. Japanese package insert of Certican tablet[http://www.info.pmda.go.jp/downfiles/ph/PDF/300242_3999022F1028_1_08.pdf]
  17. Basic Principles on Global Clinical Trials: / Pharmaceuticals and Medical Devices Agency (PMDA Notification No. 0928010). [http://www.pmda.go.jp/english/service/pdf/notifications/PFSB-ELD-0928010.pdf]
  18. Racusen LC, Colvin RB, Solez K, Mihatsch MJ, Halloran PF, Campbell PM, Cecka MJ, Cosyns JP, Demetris AJ, Fishbein MC, Fogo A, Furness P, Gibson IW, Glotz D, Hayry P, Hunsickern L, Kashgarian M, Kerman R, Magil AJ, Montgomery R, Morozumi K, Nickeleit V, Randhawa P, Regele H, Seron D, Seshan S, Sund S, Trpkov K: Antibody-mediated rejection criteria 鈥?an addition to the Banff 97 classification of renal allograft rejection. / Am J Transplant 2003, 3:708. CrossRef
  19. Coresh J, Astor BC, Greene T, Eknoyan G, Levey AS: Prevalence of chronic kidney disease and decreased kidney function in the adult US population: Third National Health and Nutrition Examination Survey. / Am J Kidney Dis 2003, 41:1. CrossRef
  20. Hariharan S, McBride MA, Cherikh WS, Tolleris CB, Bresnahan BA, Johnson CP: Post-transplant renal function in the first year predicts long-term kidney transplant survival. / Kidney Int 2002, 62:311. CrossRef
  21. Morozumi K, Thiel G, Albert FW, Banfi G, Gudat F, Mihatsch MJ: Studies on morphological outcome of cyclosporine-associated arteriolopathy after discontinuation of cyclosporine in renal allografts. / Clin Nephrol 1992, 38:1鈥?.
  22. Nankivell BJ, Borrows RJ, Fung CL, O'Connell PJ, Chapman JR, Allen RD: Calcineurin inhibitor nephrotoxicity: longitudinal assessment by protocol histology. / Transplantation 2004, 78:557鈥?65. CrossRef
  23. Araki K, Turner AP, Shaffer VO, Gangappa S, Keller SA, Bachmann MF, Larsen CP, Ahmed R: mTOR regulates memory CD8 T-cell differentiation. / Nature 2009, 460:108. CrossRef
  24. Turner AP, Shaffer VO, Araki K, Martens C, Turner PL, Gangappa S, Ford ML, Ahmed R, Kirk AD, Larsen CP: Sirolimus enhances the magnitude and quality of viral-specific CD8(+) T-cell responses to vaccinia virus vaccination in rhesus macaques. / Am J Transplant 2011, 11:613. CrossRef
  25. Saemann MD, Haidinger M, Hecking M, H枚rl WH, Weichhart T: The multifunctional role of mTOR in innate immunity: implications for transplant immunity. / Am J Transplant 2009, 9:2655. CrossRef
  
• 作者单位：Kota Takahashi (11)
  Kazuharu Uchida (12)
  Norio Yoshimura (13)
  Shiro Takahara (9)
  Satoshi Teraoka (10)
  Rie Teshima (11)
  Catherine Cornu-Artis (12)
  Eiji Kobayashi (13)
  
  11. Novartis Pharma K.K, Tokyo, 106-8618, Japan
  12. Novartis Pharma AG, Basel, CH-4002, Switzerland
  13. Division of Development of Advanced Treatment, Center for Development of Advanced Medical Technology, Jichi Medical University, Tochigi, 329-0498, Japan
  9. Department of Advanced Technology for Transplantation, Osaka University Graduate School of Medicine, Osaka, 565-0871, Japan
  10. Department of Transplant Surgery, International University of Health and Welfare Atami Hospital, Shizuoka, 413-0012, Japan
  

文摘

Background No study to date has evaluated the efficacy and safety of everolimus with reduced-exposure cyclosporine in Japanese de-novo renal transplant (RTx) patients. Methods This 12-month, multicenter, open-label study randomized (1:1) 122 Japanese de-novo RTx patients to either an everolimus regimen (1.5 mg/day starting dose (target trough: 3 to 8 ng/ml) + reduced-dose cyclosporine) or a mycophenolate mofetil (MMF) regimen (2 g/day + standard dose cyclosporine). All patients received basiliximab and corticosteroids. Key endpoints at month 12 were composite efficacy failure (treated biopsy-proven acute rejection, graft loss, death, or loss to follow-up) and renal function (estimated glomerular filtration rate; Modification of Diet in Renal Disease-4). Results Clear cyclosporine exposure reduction was achieved in the everolimus group throughout the study (52% reduction at month 12). Month 12 efficacy failure rates showed everolimus 1.5 mg to be non-inferior to MMF (11.5% vs. 11.5%). The median estimated glomerular filtration rate at month 12 was 58.00 ml/minute/1.73 m2 in the everolimus group versus 55.25 ml/minute/1.73 m2 in the MMF group (P = 0.063). Overall, the incidence of adverse events was comparable between the groups with some differences in line with the known safety profile of the treatments. The everolimus group had a higher incidence of wound healing events and edema, whereas a higher rate of cytomegalovirus infections was reported in the MMF group. Conclusions This study confirmed the efficacy of everolimus 1.5 mg/day (target trough: 3 to 8 ng/ml) in Japanese RTx patients for preventing acute rejection, while allowing for substantial cyclosporine sparing. Renal function and safety findings were comparable with previous reports from other RTx populations. Trial registration ClinicalTrials.gov number: NCT00658320