- Email: [email protected]
Impact of cyclosporine on the development of immunosuppressive therapy
Impact of Cyclosporine on the Development of Immunosuppressive Therapy L. Fritsche, D. Dragun, H.H. Neumayer, and K. Budde ABSTRACT With the advent of cyclosporine (CsA) 20 years ago, graft survival increased considerably to more than 80% at 2 years posttransplant. The early formulation of CsA, Sandimmun, is effective in preventing organ rejection, although its absorption profile means it is subject to a high degree of variability. The development of a microemulsion formulation, Neoral, provided a therapy with superior efficacy in kidney, liver, and heart transplantation with an improved pharmacokinetic profile. Calcineurin inhibitors (CNIs), including CsA, have a narrow therapeutic range, so frequent blood measurements to control drug levels are required. Recent research has demonstrated that the measurement of blood CsA concentration at 2 hours postdosing—C2 monitoring— has the potential to optimize efficacy and reduce the side effects associated with CNI use. In heart and de novo kidney transplantation, C2 monitoring may help to further reduce the incidence of acute rejection, while in maintenance renal transplant recipients, C2 monitoring can help to detect overexposure and thus allows safe dose reduction, which may improve blood pressure and renal function. C2 monitoring thus facilitates a better balance between effective Neoral immunosuppression and unwanted side effects. Today, CsA remains the cornerstone of immunosuppression, and ongoing studies aim to further optimize patient management strategies with Neoral. With other trials evaluating the impact of Neoral in combination with newer therapies such as Certican, myfortic, and FTY720, the use of CsA in transplant recipients looks set to continue.
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INCE ITS LAUNCH in 1983, cyclosporine (CsA) has represented the cornerstone of immunosuppression in the transplantation setting. The effects of acute rejection and the severe side effects of early immunosuppressant drugs on patient mortality rates have greatly diminished, and successful programs have been established for the transplantation of kidney, liver, heart, pancreas, lung, and small bowel allografts.1
CYCLOSPORINE—A HISTORICAL PERSPECTIVE
CsA was discovered in 1972 in a search for biologically produced antifungal agents.2 Routine screening identified a number of immunological properties, and subsequent in vitro and in vivo assays suggested that CsA might offer advantages over the immunosuppressive drugs then in clinical use.3 Studies in various animal models showed that CsA was a powerful immunosuppressant with a good 0041-1345/04/$–see front matter doi:10.1016/j.transproceed.2003.12.038 130S
therapeutic index.4 In these models, CsA was found to suppress rejection of vascularized organ allografts.5 CLINICAL DEVELOPMENT
Human studies initially used CsA as the sole immunosuppressant from the day of transplantation.6,7 The occurrence of nephrotoxicity in a pilot study of CsA in renal allograft recipients led to a policy of deliberate hydration of patients in the perioperative phase and withholding of CsA until diuresis was achieved in the graft. Even in these early days, actuarial graft survival of 82% at both 1 and 2 years was obtained, which represented a dramatic improvement on From the Department of Nephrology, Charite´ Campus Mitte, Berlin, Germany. Address reprint requests to Lutz Fritsche, Med. Klinik m. S. Nephrologie, Charite´ Campus Mitte, 10098 Berlin, Germany. E-mail: [email protected] © 2004 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 36 (Suppl 2S), 130S⫺134S (2004)
IMPACT OF CYCLOSPORINE ON IMMUNOSUPPRESSIVE THERAPY
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the results previously obtained with azathioprine and steroids.7 Similar rates of graft survival (77.6%) were achieved with CsA plus low-dose steroids.8 These excellent findings in renal allograft recipients were also seen in liver graft recipients, with patient survival at 1.0 and 2.5 years being increased from 35% and 25% to 75% and 55%, respectively, with the use of CsA plus low-dose steroids.9 A study using CsA as the primary immunosuppressant in heart transplant recipients reported 1- and 2-year survival rates of around 80% and 70% to 75%, respectively. These results represented a significant improvement over the 1- and 2-year survival rates of 60% and 55% previously recorded without CsA.10
CsA with Neoral, and these findings were confirmed in kidney, liver, and heart transplant recipients.15
IMPROVEMENTS IN SOLID ORGAN TRANSPLANTATION WITH CYCLOSPORINE
KIDNEY TRANSPLANTATION
Sandimmun, an oil-based formulation of cyclosporine, was first approved for clinical use in 1983. In addition to the significant advance over azathioprine and corticosteroids in terms of graft and patient survival, Sandimmun demonstrated an improved tolerability profile compared with both azathioprine, which causes bone marrow depression, and continuous high-dose corticosteroids, which have a number of associated side effects, such as growth stunting, osteoporosis, and muscle wasting. This led to a shorter duration of hospitalization and more rapid rehabilitation in Sandimmun-treated patients.4 Clinical studies conducted following the introduction of Sandimmun confirmed the initial results, with 1-year graft survival rates of 70% to 80% reported for kidney and heart recipients and 60% to 65% for liver allograft recipients.11 These findings were supported by the results of a further study, which reported improved graft and patient survival at 3 years in CsA-treated patients compared with azathioprine.12 DEVELOPMENT OF CYCLOSPORINE MICROEMULSION (NEORAL)
Although Sandimmun contains dispersing agents that provide a certain level of oral absorption, its reliance on emulsification by bile led to inter- and intrapatient variability in CsA absorption. The inconsistent absorption of Sandimmun, combined with the narrow therapeutic range of CsA, made it difficult to define optimum doses to maximise efficacy and minimize nephrotoxicity.1 In liver transplant patients, the dependence of Sandimmun absorption on adequate bile flow was particularly problematic because bile secretion is initially impaired following liver transplantation.13 This variable bioavailability necessitated the use of intravenous CsA in the early transplantation period. Neoral, a microemulsion formulation of CsA, was developed in 1995. It provides the excellent immunosuppressive activity of Sandimmun with consistent absorption and pharmacokinetic predictability.14,15 Pharmacokinetic studies in healthy volunteers reported increased bioavailability of
CLINICAL IMPACT OF NEORAL IN DE NOVO AND MAINTENANCE PATIENTS
Since the introduction of Neoral, several multicenter clinical trials have demonstrated the significant impact of this advanced formulation of CsA in lowering the rates of acute rejection in de novo kidney, liver, and heart transplant recipients. Importantly, the increased systemic exposure to CsA resulting from Neoral use has not been found to translate into a higher incidence or severity of adverse events compared with Sandimmun.
Double-blind, randomized studies comparing Neoral with Sandimmun in renal transplant recipients have generally reported equivalent efficacy, with a trend toward lower CsA dosages and acute rejection rates with Neoral (Table 1).16 –21 A study in 167 de novo renal transplant recipients followed for 3 months posttransplant reported no difference in the safety or tolerability of Neoral and Sandimmun.21 However, Neoral-treated patients had significantly lower incidences of both acute rejection and multiple episodes of rejection. Studies in stable renal transplant recipients converted from Sandimmun to Neoral maintenance therapy have reported no substantial differences in acute rejection or dosage.22 In one double-blind, randomized study, data at 3 and 12 months demonstrated no significant change in CsA dosage or incidence of acute rejection in patients switching to Neoral therapy compared with those remaining on Sandimmun.16,23 A further study found that mean CsA concentrations were comparable in patients converted to Neoral and those maintained on Sandimmun throughout the 6 months of follow-up, although a greater decrease in mean CsA dose was seen with Neoral (2.8% vs 0.3%, respectively).24 Rates of biopsy-proven acute rejection (BPAR) (0.9% and 0.8%, respectively) and the incidence and severity of adverse events were similar in the Neoral and Sandimmun groups, with no difference in serum creatinine or creatinine clearance. LIVER TRANSPLANTATION
A study in de novo liver transplant patients reported a significantly lower incidence of both treated rejection and histologically confirmed rejection with Neoral at 2 weeks posttransplant (Table 1).25–29 At 1 year, similar rates of rates of graft failure and patient survival were recorded in Neoral- and Sandimmun-treated patients. No significant differences in adverse events or laboratory findings were reported. These findings confirm those of an earlier controlled study, which found a significantly lower rate of acute rejection in Neoral-treated liver transplant patients (25% vs 65%, P ⫽ .02), but no difference in the incidence or severity of adverse events.30
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FRITSCHE, DRAGUN, NEUMAYER ET AL Table 1. Effect of CsA Formulation on Incidence of Acute Rejection in De Novo Renal and Liver Transplant Recipients Incidence of Acute Rejection (%)
Organ
Reference
Neoral
Sandimmun
P
Renal
Frei et al16 Niese17 Barone et al18 Korn et al19 Lodge and Pollard20 Keown and Niese21 Grant et al25 Gradziadei et al26 Donovan27 Otto et al28 Pinson et al29
44 42 37 36 32
51 65 30 56 46
NS NS NS NS P ⬍ .05
44
61
P ⬍ .05
54 53 63 48 56
33 56 59 53 87
NS NS NS P ⬍ .05 P ⬍ .05
Liver
NS, not significant. Adapted from Levy (1999).1
The use of Neoral in pediatric de novo liver transplant patients has resulted in significantly fewer episodes of BPAR compared with Sandimmun (35.3% vs 80.0%, P ⫽ .01), indicating Neoral may be the CsA formulation of choice in this population.31 Studies in stable liver transplant recipients have reported the safety and tolerability of Neoral following conversion from Sandimmun.32,33 In one study, a mean overall dose reduction of 16% was noted 1 month postconversion.34 Switching patients to Neoral was not accompanied by any changes in the incidence or severity of adverse events, and no changes in mean serum creatinine or blood pressure values were observed. HEART TRANSPLANTATION
Studies have reported equivalent efficacy of Neoral and Sandimmun in de novo heart transplantation. In a randomized study of Neoral versus Sandimmun in de novo heart transplant recipients, the 6-month analysis found a reduced requirement for antilymphocyte antibody therapy to treat rejection, fewer ISHLT grade ⱖ 3 rejections in female patients and fewer infections in Neoral-treated patients.35 At 12 and 24 months, allograft and recipient survival were identical in the Neoral and Sandimmun groups, and no differences were noted in blood pressure values or creatinine levels.36,37 Studies in heart transplant patients converted from Sandimmun to Neoral maintenance therapy have reported lower rates of acute rejection, lower therapeutic doses, and comparable tolerability.38,39 In 81 patients switched from Sandimmun to Neoral a mean of 27 months following heart transplantation, the mean dose of Neoral was reduced by 5.5% 3 months following conversion.38 No significant effects on acute rejection or the frequency or severity of adverse events were seen. However, 10% of patients experienced increased creatinine levels, indicating a need for routine monitoring of both CsA and serum creatinine levels.
IMPROVING EFFICACY AND TOLERABILITY OF CYCLOSPORINE
The use of CNIs, such as CsA, is associated with a number of well-documented dose-related side effects, most notably acute and chronic nephrotoxicity, hypertension, and neurotoxicity.22 In addition, CNIs have a narrow therapeutic range, and frequent measurement of whole blood concentrations is important to avoid fluctuations in drug levels. Advanced monitoring techniques, such as C2 monitoring, have the potential to further reduce the incidence of acute rejection in patients receiving Neoral. C2 monitoring is a patient management tool in which the Neoral dose is adjusted based on a measurement of the blood CsA concentration 2 hours postdose as opposed to the established practice of trough level (C0) monitoring, which measures drug levels immediately postdose. C2 monitoring allows the cyclosporine exposure of each patient to be controlled individually, permitting the safe reduction of Neoral dose, which reduces CsA toxicity and improves kidney function.
DE NOVO PATIENTS
Reports of the use of C2 monitoring to profile CsA absorption in de novo kidney transplant recipients treated with Neoral have described a reduced incidence of histologically confirmed rejection in patients where optimized Neoral dosing succeeded (7% vs 37% in patients not meeting target levels).40 C2 monitoring has also demonstrated a lower overall incidence of acute rejection compared with C0 monitoring in de novo liver transplant recipients (23.6% vs 31.6%, P ⫽ .144).41 A significant reduction in the incidence of moderate-to-severe BPAR was also reported (47% vs 73%, P ⫽ .01), which is indicative of good long-term prognosis. A reduced incidence of acute rejection has also been observed in de novo heart transplant recipients managed with C2 monitoring.42
IMPACT OF CYCLOSPORINE ON IMMUNOSUPPRESSIVE THERAPY
MAINTENANCE PATIENTS
Therapeutic drug monitoring also has value in maintenance patients, in whom variable immunosuppression, drug-induced toxicity, noncompliance, and drug interactions become more prominent problems.43 The use of C2 monitoring in stable renal transplant patients previously monitored by C0 led to dose reduction in overexposed patients, resulting in improvements in renal function and blood pressure.44 C2 monitoring has also been found to result in Neoral dose reductions and improvements in clinical benefit in stable liver transplant patients.45 Conversion of maintenance liver and heart transplant patients to C2 monitoring has resulted in large improvements in renal function.46 The advantages of Neoral dose monitoring with C2 compared with C0 have also been demonstrated in stable heart transplant patients, resulting in Neoral dose reduction and a significant increase in clinical benefit (69.3% vs 43.3% of patients, P ⬍ .00001).47 In stable heart transplant patients converted from Sandimmun to Neoral, the use of C2 monitoring resulted in lower Neoral doses compared with patients managed with C0 monitoring, with no evidence of acute rejection on endomyocardial biopsies.48 THE FUTURE OF CYCLOSPORINE THERAPY—ONGOING TRIALS WITH CYCLOSPORINE
Twenty years after its launch, CsA remains a critical factor in successful organ transplantation. Ongoing trials of combination therapy with Neoral as the core immunosuppressant therapy, such as the MOST, MO2ART, LIS2T, and DIRECT trials, aim to provide updated strategies to optimize Neoral use and improve clinical outcomes in transplant patients. The introduction of newer agents that can be used in combination with CsA, such as certican, myfortic, and FTY720, offer the potential to reduce the Neoral dose further while improving rejection rates and tolerability. CONCLUSION
The introduction of cyclosporine has been a major advance in transplantation. A large body of clinical evidence is available to demonstrate that cyclosporine is an effective and well-tolerated therapy in both de novo and maintenance transplant recipients. New approaches to optimize patient management with Neoral using C2 monitoring and continuing clinical trials with adjunctive immunosuppressant agents look set to extend the value of this drug in the transplant setting. REFERENCES 1. Levy GA: Neoral/cyclosporine-based immunosuppression. Liver Transplant Surg 5(suppl 1):S37, 1999 2. Borel JF: History of the discovery of cyclosporin and of its early pharmacological development. Wien Klin Wochenschr 114: 433, 2002 3. White DJG: Cyclosporin A: clinical pharmacology and therapeutic potential. Drugs 24:322, 1982
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4. Weil C: Cyclosporin A: review of results in organ and bone-marrow transplantation in man. Med Res Rev 4:221, 1984 5. Morris PJ: Cyclosporin A: overview. Transplantation 32:349, 1981 6. Calne RY, Rolles K, White DJ, et al: Cyclosporin A initially as the only immunosuppressant in 34 recipients of cadaveric organs: 32 kidneys, 2 pancreases, and 2 livers. Lancet 2:1033, 1979 7. White DJ, Calne RY: The use of cyclosporin A immunosuppression in organ grafting. Immunol Rev 65:115, 1982 8. Starzl TE, Klintmalm GB, Weil R III, et al: Cyclosporin A and steroid therapy in sixty-six cadaver kidney recipients. Surg Gynecol Obstet 153:486, 1981 9. Starzl TE, Iwatsuki S, Van Thiel DH, et al: Evolution of liver transplantation. Hepatology 2:614, 1982 10. Oyer PE, Stinson EB, Jamieson SW, et al: Cyclosporine in cardiac transplantation: a 21/2 year follow-up. Transplant Proc 15:2546, 1983 11. Cohen DJ, Loertscher R, Rubin MF, et al: Cyclosporine: a new immunosuppressive agent for organ transplantation. Ann Intern Med 101:667, 1984 12. The Canadian Multicentre Transplant Study Group: A randomised clinical trial of cyclosporine in cadaveric renal transplantation. Analysis at 3 years. N Engl J Med 314:1219, 1986 13. Friman S, Persson H, Karlberg I, et al: The bile acid independent flow is reduced in the transplanted liver. Transplant Int 5:S163, 1992 14. Taesch S, Niese D: Safety and tolerability of a new oral formulation of cyclosporin A, Sandimmun Neoral, in renal transplant patients. Transplant Int 7(suppl 1):S263, 1994 15. Friman S, Backman L: A new microemulsion formulation of cyclosporin: pharmacokinetic and clinical features. Clin Pharmacokinet 30:181, 1996 16. Frei U, Taesch S, Niese D: Use of Sandimmun Neoral in renal transplant patients. International Sandimmun Neoral Study Group. Transplant Proc 26:2928, 1994 17. Niese D: A double-blind randomised study of Sandimmun Neoral versus Sandimmun in new renal transplant recipients: results after 12 months. Transplant Proc 27:1849, 1995 18. Barone G, Bunke CM, Choe MG Jr, et al: The safety and tolerability of cyclosporine emulsion versus cyclosporine in a randomized, double-blind comparison in primary renal allograft recipients. Neoral Study Group. Transplantation 61:968, 1996 19. Korn A, Farber L, Maibucher A, et al: Long-term experience with Sandimmun Neoral: results in de novo and stable renal transplant patients after 24-month treatment. Transplant Proc 29:2945, 1997 20. Lodge JPA, Pollard SG: Neoral vs Sandimmune: interim results of a randomised trial of efficacy and safety in preventing acute rejection in new renal transplant recipients. Transplant Proc 29:272, 1997 21. 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 54:938, 1998 22. Dunn CJ, Wagstaff AJ, Perry CM, et al: Cyclosporin: an updated review of the pharmacokinetic properties, clinical efficacy and tolerability of a microemulsion-based formulation (Neoral) in organ transplantation. Drugs 61:1957, 2001 23. Frei UA, Neumayer HH, Buchholz B, et al: Randomized, double-blind, one-year study of the safety and tolerability of cyclosporine microemulsion compared with conventional cyclosporine in renal transplant patients. International Sandimmun Neoral Study Group. Transplantation 65:1455, 1998 24. 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 62:1744, 1996
134S 25. Grant D, Rochon J, Levy GA: Comparison of the long-term tolerability, pharmacodynamics, and safety of Sandimmune and Neoral in liver transplant recipients. Transplant Proc 28:2232, 1996 26. Gradziadei IW, Wiesner RH, Marotta PJ, et al: Neoral compared to Sandimmune is associated with a decrease in histologic severity of rejection in patients undergoing primary liver transplant. Transplantation 64:726, 1997 27. Donovan J, OLN 354 Study Group: A randomised, doubleblind study of Neoral vs Sandimmune in primary liver transplant recipients with two-year follow-up. Transplantation 65:S14, 1998 28. Otto MG, Mayer AD, Clavien PA, et al: Randomized trial of cyclosporine microemulsion (Neoral) versus conventional cyclosporin in liver transplantation. MILTON study 66:1632, 1998 29. Pinson CW, Chapman WC, Wright JK, et al: Experience with Neoral versus Sandimmune in primary liver transplant recipients. Transplant Int 11:S278, 1998 30. Hemming AW, Greig PD, Cattral MS, et al: A microemulsion of cyclosporine without intravenous cyclosporine in liver transplantation. Transplantation 62:1798, 1996 31. Alvarez F, Atkison PR, Grant DR, et al: NOF-11: a one-year pediatric randomized double-blind comparison of Neoral versus Sandimmune in orthotopic liver transplantation. Transplantation 69:87, 2000 32. Baruch Y, Assy N, Kramsky R, et al: Safety of conversion from cyclosporine Sandimmune to cyclosporine Neoral in stable liver transplant patients. Transplant Proc 30:1852, 1998 33. Bilbao I, Parrilla P, Rimola A, et al: Improvement in correlation between oral dose of cyclosporine and cyclosporinemia after substitution of conventional cyclosporine by Neoral cyclosporine in 296 liver transplant patients. Transplant Proc 30:1833, 1998 34. Pollard SG, Lodge JP: Conversion from Sandimmune to Neoral in stable liver graft recipients. Transplant Proc 28:2244, 1996 35. Eisen HJ, Hobbs RE, Davis SF, et al: Safety, tolerability and efficacy of cyclosporine microemulsion in heart transplant recipients: a randomized, multicenter, double-blind comparison with the oil based formulation of cyclosporine—results at six months after transplantation. Transplantation 68:663, 1999 36. Eisen HJ, Mueller EA, Mellein B, et al: Neoral vs Sandimmune in heart transplantation: one year results of a double-blind, international study. Transplantation 67:S7, (abstract), 1999
FRITSCHE, DRAGUN, NEUMAYER ET AL 37. Eisen HJ, Hobbs RE, Davis SF, et al: Safety, tolerability, and efficacy of cyclosporine microemulsion in heart transplant recipients: a randomized, multicenter, double-blind comparison with the oil-based formulation of cyclosporine—results at 24 months after transplantation. Transplantation 71:70, 2001 38. Dorent R, Albat B, Baladier V, et al: French multicenter study of Neoral conversion in heart transplant patients. Transplant Proc 29:2326, 1997 39. Yonan NA, Aziz T, el-Gamel A, et al: Long-term safety and efficacy of Neoral in heart transplantation. Transplant Proc 30: 1906, 1998 40. Levy GA: C2 monitoring strategy for optimising cyclosporin immunosuppression from the Neoral formulation. BioDrugs 15: 279, 2001 41. Levy G, Burra P, Cavallari A, et al: Improved clinical outcomes for liver transplant recipients using cyclosporine monitoring based on 2-hr post-dose levels (C2). Transplantation 73:953, 2002 42. Cantarovich M, Giannetti N, Cecere R: Impact of cyclosporine 2-h level and mycophenolate mofetil dose on clinical outcomes in de novo heart transplant patients receiving anti-thymocyte globulin induction. Clin Transplant 17:144, 2003 43. Levy GA: Neoral use in the liver transplant recipient. Transplant Proc 32(suppl 3A):2S, 2000 44. Cole E, Maham N, Cardella C, et al: Clinical benefits of Neoral C2 monitoring in the long-term management of renal transplant recipients. Transplantation 75:2086, 2003 45. Cantarovich M, Barkun JS, Tchervenkov JI, et al: Comparison of Neoral dose monitoring with cyclosporine trough levels versus 2-hr postdose levels in stable liver transplant patients. Transplantation 66:1621, 1998 46. Oellerich M, Armstrong VW: Two-hour cyclosporine concentration determination: an appropriate tool to monitor Neoral therapy? Ther Drug Monit 24:40, 2002 47. Cantarovich M, Elstein E, de Varennes B, et al: Clinical benefit of Neoral dose monitoring with cyclosporine 2-hr post-dose levels compared with trough levels in stable heart transplant patients. Transplantation 68:1839, 1999 48. Cantarovich M, Besner JG, Barkun JS, et al: Two-hour cyclosporine level determination is the appropriate tool to monitor Neoral therapy. Clin Transplant 12:243, 1998
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INCE ITS LAUNCH in 1983, cyclosporine (CsA) has represented the cornerstone of immunosuppression in the transplantation setting. The effects of acute rejection and the severe side effects of early immunosuppressant drugs on patient mortality rates have greatly diminished, and successful programs have been established for the transplantation of kidney, liver, heart, pancreas, lung, and small bowel allografts.1
CYCLOSPORINE—A HISTORICAL PERSPECTIVE
CsA was discovered in 1972 in a search for biologically produced antifungal agents.2 Routine screening identified a number of immunological properties, and subsequent in vitro and in vivo assays suggested that CsA might offer advantages over the immunosuppressive drugs then in clinical use.3 Studies in various animal models showed that CsA was a powerful immunosuppressant with a good 0041-1345/04/$–see front matter doi:10.1016/j.transproceed.2003.12.038 130S
therapeutic index.4 In these models, CsA was found to suppress rejection of vascularized organ allografts.5 CLINICAL DEVELOPMENT
Human studies initially used CsA as the sole immunosuppressant from the day of transplantation.6,7 The occurrence of nephrotoxicity in a pilot study of CsA in renal allograft recipients led to a policy of deliberate hydration of patients in the perioperative phase and withholding of CsA until diuresis was achieved in the graft. Even in these early days, actuarial graft survival of 82% at both 1 and 2 years was obtained, which represented a dramatic improvement on From the Department of Nephrology, Charite´ Campus Mitte, Berlin, Germany. Address reprint requests to Lutz Fritsche, Med. Klinik m. S. Nephrologie, Charite´ Campus Mitte, 10098 Berlin, Germany. E-mail: [email protected] © 2004 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 36 (Suppl 2S), 130S⫺134S (2004)
IMPACT OF CYCLOSPORINE ON IMMUNOSUPPRESSIVE THERAPY
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the results previously obtained with azathioprine and steroids.7 Similar rates of graft survival (77.6%) were achieved with CsA plus low-dose steroids.8 These excellent findings in renal allograft recipients were also seen in liver graft recipients, with patient survival at 1.0 and 2.5 years being increased from 35% and 25% to 75% and 55%, respectively, with the use of CsA plus low-dose steroids.9 A study using CsA as the primary immunosuppressant in heart transplant recipients reported 1- and 2-year survival rates of around 80% and 70% to 75%, respectively. These results represented a significant improvement over the 1- and 2-year survival rates of 60% and 55% previously recorded without CsA.10
CsA with Neoral, and these findings were confirmed in kidney, liver, and heart transplant recipients.15
IMPROVEMENTS IN SOLID ORGAN TRANSPLANTATION WITH CYCLOSPORINE
KIDNEY TRANSPLANTATION
Sandimmun, an oil-based formulation of cyclosporine, was first approved for clinical use in 1983. In addition to the significant advance over azathioprine and corticosteroids in terms of graft and patient survival, Sandimmun demonstrated an improved tolerability profile compared with both azathioprine, which causes bone marrow depression, and continuous high-dose corticosteroids, which have a number of associated side effects, such as growth stunting, osteoporosis, and muscle wasting. This led to a shorter duration of hospitalization and more rapid rehabilitation in Sandimmun-treated patients.4 Clinical studies conducted following the introduction of Sandimmun confirmed the initial results, with 1-year graft survival rates of 70% to 80% reported for kidney and heart recipients and 60% to 65% for liver allograft recipients.11 These findings were supported by the results of a further study, which reported improved graft and patient survival at 3 years in CsA-treated patients compared with azathioprine.12 DEVELOPMENT OF CYCLOSPORINE MICROEMULSION (NEORAL)
Although Sandimmun contains dispersing agents that provide a certain level of oral absorption, its reliance on emulsification by bile led to inter- and intrapatient variability in CsA absorption. The inconsistent absorption of Sandimmun, combined with the narrow therapeutic range of CsA, made it difficult to define optimum doses to maximise efficacy and minimize nephrotoxicity.1 In liver transplant patients, the dependence of Sandimmun absorption on adequate bile flow was particularly problematic because bile secretion is initially impaired following liver transplantation.13 This variable bioavailability necessitated the use of intravenous CsA in the early transplantation period. Neoral, a microemulsion formulation of CsA, was developed in 1995. It provides the excellent immunosuppressive activity of Sandimmun with consistent absorption and pharmacokinetic predictability.14,15 Pharmacokinetic studies in healthy volunteers reported increased bioavailability of
CLINICAL IMPACT OF NEORAL IN DE NOVO AND MAINTENANCE PATIENTS
Since the introduction of Neoral, several multicenter clinical trials have demonstrated the significant impact of this advanced formulation of CsA in lowering the rates of acute rejection in de novo kidney, liver, and heart transplant recipients. Importantly, the increased systemic exposure to CsA resulting from Neoral use has not been found to translate into a higher incidence or severity of adverse events compared with Sandimmun.
Double-blind, randomized studies comparing Neoral with Sandimmun in renal transplant recipients have generally reported equivalent efficacy, with a trend toward lower CsA dosages and acute rejection rates with Neoral (Table 1).16 –21 A study in 167 de novo renal transplant recipients followed for 3 months posttransplant reported no difference in the safety or tolerability of Neoral and Sandimmun.21 However, Neoral-treated patients had significantly lower incidences of both acute rejection and multiple episodes of rejection. Studies in stable renal transplant recipients converted from Sandimmun to Neoral maintenance therapy have reported no substantial differences in acute rejection or dosage.22 In one double-blind, randomized study, data at 3 and 12 months demonstrated no significant change in CsA dosage or incidence of acute rejection in patients switching to Neoral therapy compared with those remaining on Sandimmun.16,23 A further study found that mean CsA concentrations were comparable in patients converted to Neoral and those maintained on Sandimmun throughout the 6 months of follow-up, although a greater decrease in mean CsA dose was seen with Neoral (2.8% vs 0.3%, respectively).24 Rates of biopsy-proven acute rejection (BPAR) (0.9% and 0.8%, respectively) and the incidence and severity of adverse events were similar in the Neoral and Sandimmun groups, with no difference in serum creatinine or creatinine clearance. LIVER TRANSPLANTATION
A study in de novo liver transplant patients reported a significantly lower incidence of both treated rejection and histologically confirmed rejection with Neoral at 2 weeks posttransplant (Table 1).25–29 At 1 year, similar rates of rates of graft failure and patient survival were recorded in Neoral- and Sandimmun-treated patients. No significant differences in adverse events or laboratory findings were reported. These findings confirm those of an earlier controlled study, which found a significantly lower rate of acute rejection in Neoral-treated liver transplant patients (25% vs 65%, P ⫽ .02), but no difference in the incidence or severity of adverse events.30
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FRITSCHE, DRAGUN, NEUMAYER ET AL Table 1. Effect of CsA Formulation on Incidence of Acute Rejection in De Novo Renal and Liver Transplant Recipients Incidence of Acute Rejection (%)
Organ
Reference
Neoral
Sandimmun
P
Renal
Frei et al16 Niese17 Barone et al18 Korn et al19 Lodge and Pollard20 Keown and Niese21 Grant et al25 Gradziadei et al26 Donovan27 Otto et al28 Pinson et al29
44 42 37 36 32
51 65 30 56 46
NS NS NS NS P ⬍ .05
44
61
P ⬍ .05
54 53 63 48 56
33 56 59 53 87
NS NS NS P ⬍ .05 P ⬍ .05
Liver
NS, not significant. Adapted from Levy (1999).1
The use of Neoral in pediatric de novo liver transplant patients has resulted in significantly fewer episodes of BPAR compared with Sandimmun (35.3% vs 80.0%, P ⫽ .01), indicating Neoral may be the CsA formulation of choice in this population.31 Studies in stable liver transplant recipients have reported the safety and tolerability of Neoral following conversion from Sandimmun.32,33 In one study, a mean overall dose reduction of 16% was noted 1 month postconversion.34 Switching patients to Neoral was not accompanied by any changes in the incidence or severity of adverse events, and no changes in mean serum creatinine or blood pressure values were observed. HEART TRANSPLANTATION
Studies have reported equivalent efficacy of Neoral and Sandimmun in de novo heart transplantation. In a randomized study of Neoral versus Sandimmun in de novo heart transplant recipients, the 6-month analysis found a reduced requirement for antilymphocyte antibody therapy to treat rejection, fewer ISHLT grade ⱖ 3 rejections in female patients and fewer infections in Neoral-treated patients.35 At 12 and 24 months, allograft and recipient survival were identical in the Neoral and Sandimmun groups, and no differences were noted in blood pressure values or creatinine levels.36,37 Studies in heart transplant patients converted from Sandimmun to Neoral maintenance therapy have reported lower rates of acute rejection, lower therapeutic doses, and comparable tolerability.38,39 In 81 patients switched from Sandimmun to Neoral a mean of 27 months following heart transplantation, the mean dose of Neoral was reduced by 5.5% 3 months following conversion.38 No significant effects on acute rejection or the frequency or severity of adverse events were seen. However, 10% of patients experienced increased creatinine levels, indicating a need for routine monitoring of both CsA and serum creatinine levels.
IMPROVING EFFICACY AND TOLERABILITY OF CYCLOSPORINE
The use of CNIs, such as CsA, is associated with a number of well-documented dose-related side effects, most notably acute and chronic nephrotoxicity, hypertension, and neurotoxicity.22 In addition, CNIs have a narrow therapeutic range, and frequent measurement of whole blood concentrations is important to avoid fluctuations in drug levels. Advanced monitoring techniques, such as C2 monitoring, have the potential to further reduce the incidence of acute rejection in patients receiving Neoral. C2 monitoring is a patient management tool in which the Neoral dose is adjusted based on a measurement of the blood CsA concentration 2 hours postdose as opposed to the established practice of trough level (C0) monitoring, which measures drug levels immediately postdose. C2 monitoring allows the cyclosporine exposure of each patient to be controlled individually, permitting the safe reduction of Neoral dose, which reduces CsA toxicity and improves kidney function.
DE NOVO PATIENTS
Reports of the use of C2 monitoring to profile CsA absorption in de novo kidney transplant recipients treated with Neoral have described a reduced incidence of histologically confirmed rejection in patients where optimized Neoral dosing succeeded (7% vs 37% in patients not meeting target levels).40 C2 monitoring has also demonstrated a lower overall incidence of acute rejection compared with C0 monitoring in de novo liver transplant recipients (23.6% vs 31.6%, P ⫽ .144).41 A significant reduction in the incidence of moderate-to-severe BPAR was also reported (47% vs 73%, P ⫽ .01), which is indicative of good long-term prognosis. A reduced incidence of acute rejection has also been observed in de novo heart transplant recipients managed with C2 monitoring.42
IMPACT OF CYCLOSPORINE ON IMMUNOSUPPRESSIVE THERAPY
MAINTENANCE PATIENTS
Therapeutic drug monitoring also has value in maintenance patients, in whom variable immunosuppression, drug-induced toxicity, noncompliance, and drug interactions become more prominent problems.43 The use of C2 monitoring in stable renal transplant patients previously monitored by C0 led to dose reduction in overexposed patients, resulting in improvements in renal function and blood pressure.44 C2 monitoring has also been found to result in Neoral dose reductions and improvements in clinical benefit in stable liver transplant patients.45 Conversion of maintenance liver and heart transplant patients to C2 monitoring has resulted in large improvements in renal function.46 The advantages of Neoral dose monitoring with C2 compared with C0 have also been demonstrated in stable heart transplant patients, resulting in Neoral dose reduction and a significant increase in clinical benefit (69.3% vs 43.3% of patients, P ⬍ .00001).47 In stable heart transplant patients converted from Sandimmun to Neoral, the use of C2 monitoring resulted in lower Neoral doses compared with patients managed with C0 monitoring, with no evidence of acute rejection on endomyocardial biopsies.48 THE FUTURE OF CYCLOSPORINE THERAPY—ONGOING TRIALS WITH CYCLOSPORINE
Twenty years after its launch, CsA remains a critical factor in successful organ transplantation. Ongoing trials of combination therapy with Neoral as the core immunosuppressant therapy, such as the MOST, MO2ART, LIS2T, and DIRECT trials, aim to provide updated strategies to optimize Neoral use and improve clinical outcomes in transplant patients. The introduction of newer agents that can be used in combination with CsA, such as certican, myfortic, and FTY720, offer the potential to reduce the Neoral dose further while improving rejection rates and tolerability. CONCLUSION
The introduction of cyclosporine has been a major advance in transplantation. A large body of clinical evidence is available to demonstrate that cyclosporine is an effective and well-tolerated therapy in both de novo and maintenance transplant recipients. New approaches to optimize patient management with Neoral using C2 monitoring and continuing clinical trials with adjunctive immunosuppressant agents look set to extend the value of this drug in the transplant setting. REFERENCES 1. Levy GA: Neoral/cyclosporine-based immunosuppression. Liver Transplant Surg 5(suppl 1):S37, 1999 2. Borel JF: History of the discovery of cyclosporin and of its early pharmacological development. Wien Klin Wochenschr 114: 433, 2002 3. White DJG: Cyclosporin A: clinical pharmacology and therapeutic potential. Drugs 24:322, 1982
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