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Saudi Journal of Kidney Diseases and Transplantation
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EDITORIAL Table of Contents   
Year : 2006  |  Volume : 17  |  Issue : 2  |  Page : 149-152
Switching Immunosuppressive Drugs in Kidney Transplant Recipients: "Show Me the Evidence"


Transplantation Research Center (TRC), Brigham and Women’s Hospital and Children’s Hospital Boston, Harvard Medical School, Boston, MA, USA

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How to cite this article:
Ansari MJ, Sayegh MH. Switching Immunosuppressive Drugs in Kidney Transplant Recipients: "Show Me the Evidence". Saudi J Kidney Dis Transpl 2006;17:149-52

How to cite this URL:
Ansari MJ, Sayegh MH. Switching Immunosuppressive Drugs in Kidney Transplant Recipients: "Show Me the Evidence". Saudi J Kidney Dis Transpl [serial online] 2006 [cited 2020 Jun 5];17:149-52. Available from: http://www.sjkdt.org/text.asp?2006/17/2/149/35782
Kidney transplantation is now firmly established as the treatment of choice for most patients with End Stage Renal Disease (ESRD). [1] Its success is by and large the result of utilization of increasingly potent immuno­suppressive medications for the prevention of rejection. [2] Whilst the armamentarium of increasingly powerful immunosuppressive drugs is growing, the need for indefinite, maintenance immunosuppression to prevent acute and chronic rejection remains. [3] Historically, the advent of generic formulations has been a major development in therapeutics and pharmacoeconomics, including in the field of immunosuppressive drugs in transplantation. In this critical area of medicine, in which survival of the organ and in many cases the recipient are at stake, there has been an ongoing debate as to whether the generic formulations must be held to a higher standard than is usually applied by the regulatory agencies for generic drugs. Mere demonstration of bioequivalence in young healthy volunteers may be an inadequate criterion. Indeed, it has been argued that since the modern immunosuppressive agents have a complex pharmacokinetic profile, pharmacokinetics and safety data in different populations, and perhaps even efficacy data should be the standard on which approval is based. [4] Nonetheless several generic formu­lations of the calcineurin inhibitor cyclosporine have been introduced and are currently being widely used in organ transplant recipients. [5],[6]

A somewhat related but perhaps more complex issue in immunosuppressive drug therapy in transplantation is the introduction of modified formulations and/or new agents belonging to the same class as the established agents (calcineurin inhibitors, purine synthesis inhibitor, and mTOR inhibitors). This has given rise to a new challenge for the physician caring for the transplant recipients. The first two immunosuppressive drugs of this class of the so called "it too drugs" to be approved by the regulatory authorities in many countries are "Neoral", a microemulsion formulation of cyclosporine, and tacrolimus, also a calcineurin inhibitor. It has been demonstrated that the microemulsion formulation has clear pharmacokinetic superiority over the original one, [7],[8] and thus it is being widely used to prevent rejection in clinical organ transplant recipients. In addition, tacrolimus has been shown to further reduce acute rejection rates and exhibit a somewhat different side effects profile than cyclosporine, [9],[10] and is also currently being widely used as part of multi-drug regimens of maintenance immuno­suppression in transplant recipients.

More recently, two new "it too drugs" have been introduced for clinical use in many countries around the world including the purine synthesis inhibitor Enteric-coated Mycophenolate Sodium (EC-MPS) [11],[12],[13] and the mTOR inhibitor Everolimus [14],[15] (not approved in the US yet). Amidst this complex repertoire of immunosuppressive drugs and combinations thereof, the transplant physician faces the dilemma of choosing the right medication for his/her patients. This is a complex predicament since it involves two questions; first, whether de novo transplant recipients should be started on such new agents, and second, whether previous recipients should be switched to the new formulations. One would think that the answer should be relatively easy and should be based on the evidence from well-conducted randomized clinical trials. However, it has been sometimes difficult to draw clear conclusions from the transplant literature concerning immuno­suppressive drugs because of suboptimal quality of trial design and reporting. [16],[17] For instance, meta-analyses of randomized controlled trials are being performed decades after the introduction of agents such as cyclosporine and tacrolimus (FK506), which belong to the same class of drugs, to ascertain whether they have distinct toxicity and perhaps efficacy profiles. [18] Fuelling this confusion also are articles making recommendations that may not be entirely based on sound and clear data. One such article was recently published in this journal, on the comparison between EC­MPS and Mycophenolate Mofetil (MMF); the author concludes that "EC-MPS does represent an alternative to the significant number of patients suffering from the common gastrointestinal intolerance reported with MMF". [19] Whilst the magnitude of the problem is significant, in that around half of the patients receiving MMF report gastrointestinal symptoms, [20] clearly, the conclusion that EC-MPS represents an alternative to MMF is not supported by the results of the reported trials. Further, the author reports >10% and up to 36% incidence of diarrhea in patients treated with EC-MPS and MMF respectively, whereas in fact the incidence of gastrointestinal adverse effects (GI-AE), in reported studies, varied between 30% to 80%. Furthermore, although a lower rise in the GI-AE severity score from baseline and fewer dose reductions or dose discontinuations in response to GI­AE were observed in recipients treated with EC-MPS as compared with the MMF group, these differences were not statistically signi­ficant, and none of the studies were specifically powered to test this outcome. [11],[13] At best, the available data allows us to conclude non­inferiority of the efficacy of EC-MPS compared to MMF. [21] It is also likely that the GI-AE of MMF are due to the systemic effects of mycophenolic acid (MPA), and not simply a local GI effect, since the GI-AE were not avoided but in fact accentuated by the higher blood levels of MPA following intravenous administration of MMF. [22] Interestingly, it is important to note that the pharmacokinetics of EC-MPS are different from those of MMF. As expected with an enteric-coated formulation, the onset of MPA absorption with EC-MPS was delayed compared with the MMF formulation (median Tmax 2.5 versus 1.0 hour, respectively) but mean Cmax was slightly higher for EC-MPS. The MPA AUC for both formulations, however, was comparable. [23] EC-MPS is primarily absorbed in the intestine and undergoes significant enterohepatic recirculation. [24],[25] Factors affecting gastric emptying, such as food intake, type of meal, diabetic and other autonomic neuropathy will likely impact on the pharmaco­kinetics of enteric coated formulations, and those that undergo significant enterohepatic recirculation. [26] Further, results of EC-MPS in the reported adult renal transplant population cannot be extended to other patient populations (diabetics, pediatrics, elderly, etc.), or other organ transplant recipients, especially liver recipients. For these reasons and due to the lack of long-term efficacy data with EC-MPS, the US Prescribing Information specifically states that the two preparations cannot be used interchangeably. [27] Clearly, a well-designed definitive controlled trial comparing the two drugs in transplant recipients to clearly address the issue of GI-AE is required.

Finally, the economic impact of introduction of new "it too drugs" for clinical use adds to the complexity and confusion of the matter. When it comes to switching immunosuppressive drugs the transplant professionals should not be shy from asking the important question: "show me the evidence". We believe that there should be a hierarchy of questions that should be considered when choosing a particular immunosuppressive agent. These questions relate to the efficacy, safety, tole­rability and cost of the agent. The answers should be based on clear evidence from well­designed clinical trials. Economic conside­rations should also be entertained, but only when the questions of long-term safety and efficacy have been satisfactorily answered.

 
   References Top

1.Sayegh MH, Carpenter CB. Transplantation 50 years later-progress, challenges, and promises. N Engl J Med 2004;351(26):2761-6.  Back to cited text no. 1    
2.Denton MD, Magee CC, Sayegh MH. Immunosuppressive strategies in transplant­ation. Lancet 1999;353(9158):1083-91.  Back to cited text no. 2    
3.Ansari MJ, Sayegh MH. Clinical transplant­ation tolerance: the promise and challenges. Kidney Int 2004;65(5):1560-3.  Back to cited text no. 3    
4.Sabatini S, Ferguson RM, Helderman JH, Hull AR, Kirkpatrick BS, Barr WH. Drug substitution in transplantation: a National Kidney Foundation White Paper. Am J Kidney Dis 1999;33(2):389-97.  Back to cited text no. 4    
5.Cattaneo D, Perico N, Remuzzi G. Generic cyclosporine formulations: more open questions than answers. Transpl Int 2005;18(4):371-8.  Back to cited text no. 5    
6.Johnston A, Belitsky P, Frei U, et al. Potential clinical implications of substitution of generic cyclosporine formulations for cyclosporine microemulsion (Neoral) in transplant recipients. Eur J Clin Pharmacol 2004;60(6):389-95.  Back to cited text no. 6    
7.Keown P, Niese D. Cyclosporine micro­emulsion increases drug exposure and reduces acute rejection without incremental toxicity in de novo renal transplantation. International Sandimmun Neoral Study Group. Kidney Int 1998;54(3):938-44.  Back to cited text no. 7    
8.Keown P, Landsberg D, Halloran P, et al. A randomized, prospective multicenter pharmaco­epidemiologic study of cyclosporine micro­emulsion in stable renal graft recipients. Report of the Canadian Neoral Renal Transplantation Study Group. Transplant­ation 1996;62(12):1744-52.  Back to cited text no. 8    
9.Mayer AD, Dmitrewski J, Squifflet JP, et al. Multicenter randomized trial comparing tacrolimus (FK506) and cyclosporine in the prevention of renal allograft rejection: a report of the European Tacrolimus Multicenter Renal Study Group. Transplantation 1997; 64(3):436-43.  Back to cited text no. 9    
10.Pirsch JD, Miller J, Deierhoi MH, Vincenti F, Filo RS. A comparison of tacrolimus (FK506) and cyclosporine for immuno­suppression after cadaveric renal transplant­ation. FK506 Kidney Transplant Study Group. Transplantation 1997;63(7):977-83.  Back to cited text no. 10    
11.Budde K, Curtis J, Knoll G, et al. Enteric­coated mycophenolate sodium can be safely administered in maintenance renal trans­plant patients: results of a 1-year study. Am J Transplant 2004;4(2):237-43.  Back to cited text no. 11    
12.Budde K, Knoll G, Curtis J, et al. Safety and efficacy after conversion from myco­phenolate mofetil to enteric-coated myco­phenolate sodium: results of a 1-year extension study. Transplant Proc 2005;37(2):912-5.  Back to cited text no. 12    
13.Salvadori M, Holzer H, de Mattos A, et al. Enteric-coated mycophenolate sodium is therapeutically equivalent to mycophenolate mofetil in de novo renal transplant patients. Am J Transplant 2004;4(2):231-6.  Back to cited text no. 13    
14.Vitko 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(10):2521-30.  Back to cited text no. 14    
15.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.  Back to cited text no. 15    
16.Curtis JJ, Kaplan B. Transplant immuno­suppressive drug trials on trial. Am J Transplant 2004;4(5):671-2.  Back to cited text no. 16    
17.Fritsche L, Einecke G, Fleiner F, Dragun D, Neumayer HH, Budde K. Reports of large immunosuppression trials in kidney trans­plantation: room for improvement. Am J Transplant 2004;4(5):738-43.  Back to cited text no. 17    
18.Webster AC, Woodroffe RC, Taylor RS, Chapman JR, Craig JC. Tacrolimus versus ciclosporin as primary immunosuppression for kidney transplant recipients: meta­analysis and meta-regression of randomised trial data. BMJ 2005;331(7520):810.  Back to cited text no. 18    
19.Zolezzi M. Mycophenolate Sodium versus Mycophenolate Mofetil: a Review of Their comparative features. Saudi J Kidney Dis Transplant 2005;16(2):140-5.  Back to cited text no. 19    
20.Placebo-controlled study of mycophenolate mofetil combined with cyclosporin and corticosteroids for prevention of acute rejection. European Mycophenolate Mofetil Cooperative Study Group. Lancet 1995;345 (8961):1321-5.  Back to cited text no. 20    
21.Meier-Kriesche HU, Davies NM, Grinyo J, et al. Mycophenolate sodium does not reduce the incidence of GI adverse events compared with mycophenolate mofetil. Am J Transplant 2005;5(5):1164; author reply 1165-6.  Back to cited text no. 21    
22.Pescovitz MD, Conti D, Dunn J, et al. Intravenous mycophenolate mofetil: safety, tolerability, and pharmacokinetics. Clin Transplant 2000;14(3):179-88.  Back to cited text no. 22    
23.Tedesco-Silva H, Bastien MC, Choi L, et al. Mycophenolic acid metabolite profile in renal transplant patients receiving enteric­coated mycophenolate sodium or myco­phenolate mofetil. Transplant Proc 2005; 37(2):852-5.  Back to cited text no. 23    
24.Bullingham R, Monroe S, Nicholls A, Hale M. Pharmacokinetics and bioavailability of mycophenolate mofetil in healthy subjects after single-dose oral and intravenous administration. J Clin Pharmacol 1996; 36(4):315-24.  Back to cited text no. 24    
25.Arns W, Breuer S, Choudhury S, Tet al. Enteric-coated mycophenolate sodium delivers bioequivalent MPA exposure compared with mycophenolate mofetil. Clin Transplant 2005;19(2):199-206.  Back to cited text no. 25    
26.Kimura T, Higaki K. Gastrointestinal transit and drug absorption. Biol Pharm Bull 2002;25(2):149-64.  Back to cited text no. 26    
27.Product Monograph. Myfortic® (myco­phenolate sodium). Novartis Pharma, USA. February 2004.  Back to cited text no. 27    

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Correspondence Address:
Mohamed H Sayegh
Transplantation Research Center, Brigham and Women’s Hospital and Children’s Hospital Boston, Harvard Medical School, 221 Longwood Ave, Boston, MA 02115
USA
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PMID: 16903619

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