- Email: [email protected]
The promise of C2, simulect, and certican in heart transplantation
The Promise of C2, Simulect, and Certican in Heart Transplantation D. H. Delgado and H. J. Ross ABSTRACT Immunosuppressive therapy in clinical transplantation has evolved from general nonspecific suppression of the immune system to selective blockade of intracellular immune events, maximizing graft tolerance while minimizing toxicity. Cyclosporine 2-hour postdose level monitoring has been recommended as the single most sensitive sampling point for assessment of the area under the curve, and predictor of clinical outcomes in heart transplantation. Strategies for monitoring immunosuppressive drugs to improve efficacy without increased toxicity are critical as we move into the 21st century. Everolimus, a derivative of rapamycin, is a macrocyclic immunosuppressive agent with antiproliferative activity that is efficacious in preventing graft vasculopathy. Agents that increase the armamentarium against rejection allowing individualized therapy tailored to minimize complications, and prevent graft vasculopathy will improve our flexibility and may translate into improved long-term outcomes.
C
ardiac transplantation is currently the treatment of choice for patients with severe end-stage congestive heart failure failing maximal medical therapy. Improvements over the past few years in organ donation, organ preservation and antirejection therapy have resulted in improved survival rates after heart transplantation.1 Longterm survival after transplant remains limited by allograft vasculopathy and complications in part related to immune therapy, eg, malignancy.2 Immunosuppressive therapy in clinical transplantation has evolved from general nonspecific immunosuppression, to selective blockade of intracellular immune events, which maximize graft tolerance, while minimizing toxicity. Although current immunosuppressive drugs have established HT as a successful procedure, the risks of opportunistic infection and rejection, as well as allograft vasculopathy and malignancy, have spurred the development of newer immunosuppressive agents and monitoring designed to reduce complications and improve efficacy. This paper outlines new developments in strategies for cyclosporine monitoring, basiliximab induction therapy, and the role of everolimus therapy in the prevention of allograft vasculopathy in cardiac transplant recipients. MONITORING OF CYCLOSPORINE IN CARDIAC TRANSPLANTATION
Cyclosporine A (CsA) is a cornerstone in immunosuppressive therapy of solid organ transplants. Survival after HT markedly increased after the introduction of CsA in the 0041-1345/04/$–see front matter doi:10.1016/j.transproceed.2004.01.009 504S
early 1980s. Therapeutic drug monitoring of CsA is routinely employed to assist dose adjustment for rejection and toxicity, to detect drug interactions, and to identify noncompliance with therapy.3 Different CsA monitoring approaches have been described in an attempt to optimize immunotherapy, to improve clinical outcomes and reduce toxicity.4 Bioavailability and exposure, measured using full area under the curve pharmacokinetic profiles, have been shown to correlate closely with freedom from acute rejection.5 Because long term sequential pharmacokinetic profiling is impractical, the trough (C0) CsA blood level has been widely accepted for long-term therapeutic monitoring.1 However, trough level CsA monitoring does not accurately reflect total drug exposure and does not correlate with individual episodes of acute rejection and/or nephrotoxicity.6 Trough CsA also correlates poorly with AUC from 0 to 12 hours and AUC from 0 to 4 hours in other solid organ transplantation.7 Cyclosporine A monitoring 2-hour postdose (C2), when initially investigated in liver and kidney transplant recipients, was found to be the single most sensitive sampling point to accurately predict the absorption profile and clinical outcomes.8 –10 Division of Cardiology and Transplant, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada. Address reprint requests to Heather Ross, MD, FRCP(C), Toronto General Hospital, 10 NU 129, 200 Elizabeth St., Toronto, Ontario, Canada M5G 2C4. © 2004 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 36 (Suppl 2S), 504S–508S (2004)
C2, SIMULECT, AND CERTICAN IN HEART TRANSPLANTS
C2 levels correlate closely with acute rejection in liver transplantation. A prospective, open label multicenter trial conducted in 307 de novo liver transplant recipients provided an important pharmacokinetic correlation between C2 and acute rejection.11 This study showed that the incidence of rejection was inversely correlated with C2 levels and that trough CsA levels correlated poorly with graft rejection. To test whether C2 single-point monitoring could be utilized to predict freedom from rejection, a nonrandomized study was conducted in de novo liver transplant recipients.12 At 1 year post-LT, 80% of patients monitored with C2 were rejection free whereas only 60% of patients monitored with C0 were rejection free. The incidence of nephrotoxicity was similar in patients monitored with C0 or C2 levels. Correlation between the area under the concentration curve, or AUC from 0 to 4 hours, and CsA C2 levels were confirmed in a population of 35 stable adult patients ⬎1 year after liver transplantation.13 In this study CsA monitoring with a C2 range from 300 to 600 ng/mL resulted in greater clinical benefit (no rejection and no increase in serum creatinine) compared to C0 or higher C2 levels. In HT, CsA C2 levels have an excellent correlation with AUC from 0 to 4 hours whereas C0 levels have a relatively poor correlation with AUC from 0 to 4 hours.14 The results of C0 versus C2 monitoring were compared in a monitoring study of 109 stable HT patients treated with CsA. Cyclosporine monitoring was initially based on C2 levels (300 – 600 ng/mL) and thereafter monitored by C0 (100 –200 ng/mL).15 Primary endpoints assessed were clinical benefits, defined as no change in left ventricular ejection fraction, mortality or an increase in serum creatinine more than 10% compared to baseline. Greater clinical benefit was observed in 69% of patients monitored by C2 versus 43% of the patients monitored by C0 (P ⫽ .0001). This benefit was attributed mostly to a lower number of patients experiencing impairment in renal function during C2 monitoring. This study failed to show improved freedom from rejection in those patients monitored by C2 levels, which may be related to the low CsA C2 target range used. C2 levels have also demonstrated correlation with absorption profiling and clinical outcomes in stable HT recipients.16 Target C2 levels at various time-points immediately after transplant or in stable HT patients have not been clearly determined. We conducted a prospective study to determine whether C0 or C2 levels better predict clinical outcomes in de novo and stable HT patients.17 We conducted a two period prospective study with paired determinations of CsA levels at C0 and C2 in 89 patients post-HT (77 males, 12 females; mean age 56 ⫾ 11.2 years), performed during regular visits to our clinic. During period I, 116 C0 –C2 paired determinations were done in 70 patients with a follow-up of 6 months. CsA dosing was monitored and adjusted according to C0 levels with investigators blinded to C2 levels. During period II, 103 C0 –C2 paired determinations were performed in 55 patients with a follow-up of 5 months. During this period CsA dosing was
505S
monitored and adjusted according to C2 levels with investigators blinded to C0 levels. The incidence of infections, level of creatinine and calculated creatinine clearance did not differ between patients monitored by C0 or by C2. Higher C2 levels were significantly associated with absence of rejection [C2 levels, 966.5 ⫾ 469.8 ng/mL versus 764.6 ⫾ 297.1 ng/mL, no rejection versus rejection, respectively (P ⫽ .037)]. C2 levels associated with absence of biopsy proven rejection, at different time-points post-HT, were as follows: from 0 to 3 months, 1350 ⫾ 371.4 ng/mL; from 3 to 6 months, 1403 ⫾ 485.2 ng/mL; from 6 to 12 months, 1175 ⫾ 415.4 ng/mL; and from 12 to 24 months, 947.7 ⫾ 470 ng/mL. Based on theses studies, the monitoring C2 levels is clinically feasible, correlates with clinical outcomes better than C0 levels, and is associated with a reduction in rejection episodes in both de novo and stable long-term HT patients. However, further studies are needed to confirm the goal range for C2 levels at various time points after transplantation. The monitoring of neoral 2 hours absorption with simulect in heart transplantation (MOTOWN) study is a 12-month, multicenter, randomized, study designed to evaluate the benefit of C2 monitoring of cyclosporine on safety and efficacy outcomes in de novo cardiac transplant recipients receiving basiliximab induction and mycophenolate mofetil (MMF) and prednisone maintenance therapy. This study will provide important information about the role of C2 monitoring in de novo cardiac transplant patients. Target C2 levels required when cyclosporine is used in conjunction with everolimus or sirolimus in cardiac transplantation require further study. SIMULECT IN CARDIAC TRANSPLANTATION
The use of induction agents in transplantation is associated with a reduction in the incidence of early rejection and graft loss.18,19 Basiliximab (Simulect®, Novartis Pharmaceuticals Corporation) is a chimeric anti-interleukin-2 receptor monoclonal antibody proven to be safe and effective in the prophylaxis of acute renal allograft rejection.20 In this study, there were significantly fewer episodes of rejection in renal transplant recipients treated with basiliximab versus those patients receiving placebo. The survival after 1-year follow-up was similar in both groups. The safety and efficacy of basiliximab was also recently demonstrated in studies conducted in kidney and liver transplantation.21–23 A Spanish study randomized 101 adult cardiac allograft recipients to either basiliximab or OKT3 induction, with cyclosporine, MMF and steroid maintenance therapy. There was a trend toward a lower incidence of adverse events with basiliximab versus OKT3 with similar rates of rejection grade ⱖ3A (29.2% versus 25.0%, respectively).24 Given the importance of achieving suitable basiliximab blood levels for effective IL-2 receptor blockade, the dilutional effect of cardiopulmonary bypass and the potential for antibody loss in the perfusion circuit must be considered when establishing basiliximab dosing protocols and timing
506S
DELGADO AND ROSS
Fig 1. Kaplan -Meier estimates of the incidence rates of efficacy failure (biopsy-proven acute rejection of grade ⱖ3 A, acute rejection associated with HDC, death, graft loss or lost to follow-up) by treatment group.
of drug delivery in HT. Currently it is recommended that basiliximab be given within 6 to 12 hours postsurgery. Controversy exists regarding how long calcineurin inhibitor use can be delayed after HT in order to minimize renal toxicity and maximize clinical effectiveness, however cyclosporine is usually started within 2 to 4 days after transplantation.25 We conducted a study to assess the safety and efficacy of basiliximab and delayed cyclosporine initiation in patients with renal dysfunction (persistent serum creatinine ⱖ200 umol/L for at least 3 months) undergoing HT. Comparisons were done using an historical group of patients who received rabbit antithymocyte serum (RATS) as induction therapy.26 No significant differences were observed in renal function or rejection with the use of either basiliximab or RATS. Cyclosporine was initiated with a mean of 7.3 days in the basiliximab group. The mean pre-OHT creatinine was 243.28 ⫾ 48.09 umol/L, at 1 week post-OHT 180.71 ⫾ 39.79 umol/L (P ⫽ .02), at 1 month 166.43 ⫾ 57.91 umol/L (P ⫽ .019), at 3 months 182.86 ⫾ 25.82 umol/L (P ⫽ .01) and at 6 months 179 ⫾ 45.04 umol/L (P ⫽ .024). No patients required long-term dialysis. The combined use of basiliximab and delayed initiation of cyclosporine in HT recipients with chronic renal dysfunction was safe and may be a reasonable therapeutic approach to minimize renal dysfunction, however, further studies are needed to demonstrate short- and long-term efficacy of basiliximab in combination with different immunosuppressive agents.
CERTICAN™ IN HEART TRANSPLANTATION
Everolimus (Certican™, Novartis Pharmaceuticals Corporation), a derivative of rapamycin, is a macrocyclic immunosuppressive agent with unique antiproliferative activity.27,28 Everolimus binds to the FK506-binding protein and arrests the cell cycle in the G1 phase. This characteristic may allow everolimus to interact synergistically with cyclosporine. Everolimus has been shown to be safe and effective in reducing acute rejection in kidney transplant patients29,30 and to be more potent than cyclosporine in extending graft survival in animals.31 A randomized, double blind, clinical trial was conducted comparing everolimus with azathioprine in de novo HT patients.32 A total of 634 patients were randomly assigned to receive 1.5 mg of everolimus per day, 3 mg of everolimus per day, or 1 to 3 mg/kg per day of azathioprine. The primary endpoint was a composite of biopsy proven acute rejection of at least grade 3A, acute rejection associated with hemodynamic compromise, death, graft loss, or loss to follow up (Fig 1). At 6 months, significantly more patients in the azathioprine group had reached the primary efficacy endpoint than in either of the everolimus groups. Intravascular ultrasound was used to assess coronary intimal proliferation at baseline and at 12 months post-HT. The average increase in the maximal intimal thickness from baseline to 12 months was smaller in the two everolimus groups than in the azathioprine group. The incidence of vasculopathy, defined as an increase in the maximal intimal thickness of at
C2, SIMULECT, AND CERTICAN IN HEART TRANSPLANTS
least 0.5 mm from baseline in at least one matched slice, was also lower in the everolimus groups (35.7% in the 1.5 mg group; 30.4% in the 3 mg group and 52.8% in the azathioprine group). The rates of cytomegalovirus infection were significantly lower in the everolimus groups than in the azathioprine group. However, serum creatinine levels were significantly higher in the two everolimus groups than in the azathioprine group, most likely related to the potentiation of cyclosporine. Everolimus is the first immunosuppressive agent proven to be efficacious in preventing vasculopathy at 12 months post-HT. Further studies are needed to determine the optimal dose of everolimus with other concomitant agents, and to determine the long-term benefits and effectiveness of everolimus in patients with established transplant vasculopathy. The use of C2 monitoring to optimize cyclosporine exposure, especially with concomitant everolimus use in order to enhance the efficacy and safety of everolimus is planned for future studies. SUMMARY
Cyclosporine A 2-hour post-dose level (C2) monitoring is the single most sensitive sampling point for assessment of the area under the curve. Ongoing studies suggest that it is a very useful predictor of clinical outcomes in heart transplantation. The combination of basiliximab and C2 monitoring may confer further protection against acute rejection. Certainly induction therapy with delayed cyclosporine initiation may prevent renal dysfunction in patients with elevated creatinine pretransplant. Everolimus is the first immunosuppressive agent shown to reduce the development of graft vasculopathy in de novo heart transplant recipients. The major limitations to long-term survival in cardiac transplant recipients remain transplant coronary artery disease and malignancy. Rejection, though decreasing in frequency, still remains common early after transplant. The patient population undergoing transplantation has evolved over the past 10 years. Patients are more likely to be critically ill, at higher status, and ventricular assist supported. Flexibility in immunosuppressive therapies allows clinicians to adjust therapy to each individual’s potential toxicity and rejection risk. Strategies for monitoring immunosuppressive drugs to improve efficacy without increased toxicity allows further refinement. The evolution of cardiac transplantation is away from protocolized treatment. Over the next 20 years improved therapies and monitoring will allow patients to be treated individually in terms of rejection, malignancy, and transplant coronary artery disease risk. REFERENCES 1. Ross H, Hendry P, Dipchand A, et al: 2001 Canadian cardiovascular society consensus conference on cardiac transplantation. Can J Cardiol 19:620, 2003 2. Hunt SA: Current status of cardiac transplantation. JAMA 280:1692, 1998
507S 3. Ginns L, Cosimi A, Morris P: Immunosuppression in Transplantation. Massachusetts: Blackwell Science; 1999 4. Valentine H: Neoral use in the cardiac transplant recipient. Transplant Proc 32:27S, 2000 5. Kasiske BL, Heim-Duthoy K, Venkateswara R, et al: The relationship between cyclosporine pharmacokinetic parameters and subsequent acute rejection in renal transplant patients. Transplantation 46:716, 1998 6. Cole EH: Neoral monitoring: limitations of trough level monitoring and the potential role of limited sampling strategies. Transplant Proc 32:1556, 2000 7. Mahalati K, Belitzky P, Sketris I, et al: Neoral monitoring by simplified sparse sampling area under the concentration-time curve: its relationship to acute rejection and cyclosporine nephrotoxicity early after kidney transplantation. Transplantation 68:55, 1999 8. Keon 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 9. Grant D, Kneteman N, Tchervenkov J, et al: Peak cyclosporine levels (Cmax) correlated with freedom from liver graft rejection: results of a prospective, randomized comparison of neural and sandimmune for liver transplantation (NOF-8). Transplantation 67:1133, 1999 10. Mahalati K, Belitsky P, Sketris I, et al: Neoral monitoring by simplified sparse sampling area under the concentration-time curve. Transplantation 68:55, 1999 11. Levy G, Burra P, Cavallari A, et al: Improved clinical outcomes for liver transplant recipients using cyclosporine based on 2-hr post-dose levels (C2). Transplantation 73:840, 2002 12. Levy G: Relationship of pharmacokinetics to clinical outcomes. Transplant Proc 31:1654, 1999 13. Cantarovich M, Barkun J, Tchervenkov J, et al: Comparison of neoral dose monitoring with cyclosporine trough levels versus 2hr postdose levels in stable liver transplant patients. Transplantation 66:1621, 1998 14. Cantarovich M, Barkun J, Tchervenkov J, et al: Comparison of neoral dose monitoring with cyclosporine trough levels versus 2hr postdose levels in stable liver transplant patients. Transplantation 66:1621, 1998 15. Cantarovich M, Elstein E, Varennes B, et al: Clinical benefit of neural dose monitorin with cyclosporine 2-hr post-dose levels compared with trough levels in stable heart transplant patients. Transplantation 68:1839, 1999 16. 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 17. Delgado D, Rao V, Cusimano RJ, et al: Monitoring of cyclosporine 2-hr post-dose and trough levels in heart transplantation. J Heart Lung Transp 21:102, 2002 18. Carrier M, White M, Perrault LP, et al: A 10-year experience with intravenous thymoglobulin in induction of immunosuppression following heart transplantation. J Heart Lung Transplant 18:1218, 1999 19. 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 20. Kahan BD, Rajagopalan PR, Hall M: Reduction of the occurrence of acute cellular rejection among renal allograft recipients treated with basiliximab, a chimeric anti-ionterleukin-2 receptor monoclonal antibody. United States Simulect Renal Study Group. Transplantation 67:276, 1999 21. Sollinger H, Kaplan B, Pescovitz MD, et al: Basiliximab versus antithymocyte globulin for prevention of acute renal allograft rejection. Transplantation 72:1915, 2001
508S 22. Matl I, Bachleda P, Lao M, et al: Safety and efficacy of an alternative basiliximab (Simulect) regimen after renal transplantation: administration of a single mf dose on the first postoperative day in patients receiving triple therapy with azathioprine. Transpl Int 16:45, 2003 23. Lawn JG, Davies EA, Mouad G, et al: Randomized doubleblind study of immunoprophylaxis with basiliximax, a chimeric anti-interleukin-2 receptor monoclonal antibody, in combination with mycophenolate mofetil-containing triple therapy in renal transplantation. Transplantation 75:37, 2003 24. Crespo-Leiro MG, Rodriguez-Lambert JL, Segovia JL, et al: Study of the safety and tolerability of Simulect® (basiliximab) versus OKT3 in heart transplantation. J Heart Lung Transplant 22:S141, 2003 25. Kirklin JK, Young JB, McGiffin DC: Heart transplantation. New York: Churchill Livingstone; 2002 26. Delgado DH, Miriuka S, Cusimano RJ, et al: Use of basiliximab and cyclosporine in heart transplant patients with preoperative renal dysfunction. J Heart Lung Transplant (in press)
DELGADO AND ROSS 27. Schuler W, Sedrani R, Cottens S, et al: SDZ RAD, a new rapamycin derivative: pharmacological properties in vitro and in vivo. Transplantation 64:36, 1997 28. Schuurman HJ, Cottens S, Fuchs S, et al: SDZ RAD, new rapamycin derivative: synergism with cyclosporine. Transplantation 64:32, 1997 29. Neumayer HH, Paradis K, Korn A, et al: Entry-into-human study with the novel immunosuppressant SDZ RAD in stable renal transplant recipients. Br J Clin Pharmacol 48:69, 1999 30. Kahan BD, Kaplan B, Lorber MI, et al: RAD in de novo renal transplantation: comparison of three doses on the incidence and severity of acute rejection. Transplantation 71:1400, 2001 31. Nikolova Z, Hof A, Baumlin Y, et al: Efficacy of SDZ RAD compared with CsA monotherapy and combined Rad/FTY720 treatment in a murine cardiac allotransplantation model. Transpl Immunol 9:43, 2001 32. Eisen HJ, Tuzcu EM, Dorent R, et al: Everolimus for the prevention of allograft rejection and vasculopathy in cardiac transplant recipients. N Engl J Med 349:847, 2003
C
ardiac transplantation is currently the treatment of choice for patients with severe end-stage congestive heart failure failing maximal medical therapy. Improvements over the past few years in organ donation, organ preservation and antirejection therapy have resulted in improved survival rates after heart transplantation.1 Longterm survival after transplant remains limited by allograft vasculopathy and complications in part related to immune therapy, eg, malignancy.2 Immunosuppressive therapy in clinical transplantation has evolved from general nonspecific immunosuppression, to selective blockade of intracellular immune events, which maximize graft tolerance, while minimizing toxicity. Although current immunosuppressive drugs have established HT as a successful procedure, the risks of opportunistic infection and rejection, as well as allograft vasculopathy and malignancy, have spurred the development of newer immunosuppressive agents and monitoring designed to reduce complications and improve efficacy. This paper outlines new developments in strategies for cyclosporine monitoring, basiliximab induction therapy, and the role of everolimus therapy in the prevention of allograft vasculopathy in cardiac transplant recipients. MONITORING OF CYCLOSPORINE IN CARDIAC TRANSPLANTATION
Cyclosporine A (CsA) is a cornerstone in immunosuppressive therapy of solid organ transplants. Survival after HT markedly increased after the introduction of CsA in the 0041-1345/04/$–see front matter doi:10.1016/j.transproceed.2004.01.009 504S
early 1980s. Therapeutic drug monitoring of CsA is routinely employed to assist dose adjustment for rejection and toxicity, to detect drug interactions, and to identify noncompliance with therapy.3 Different CsA monitoring approaches have been described in an attempt to optimize immunotherapy, to improve clinical outcomes and reduce toxicity.4 Bioavailability and exposure, measured using full area under the curve pharmacokinetic profiles, have been shown to correlate closely with freedom from acute rejection.5 Because long term sequential pharmacokinetic profiling is impractical, the trough (C0) CsA blood level has been widely accepted for long-term therapeutic monitoring.1 However, trough level CsA monitoring does not accurately reflect total drug exposure and does not correlate with individual episodes of acute rejection and/or nephrotoxicity.6 Trough CsA also correlates poorly with AUC from 0 to 12 hours and AUC from 0 to 4 hours in other solid organ transplantation.7 Cyclosporine A monitoring 2-hour postdose (C2), when initially investigated in liver and kidney transplant recipients, was found to be the single most sensitive sampling point to accurately predict the absorption profile and clinical outcomes.8 –10 Division of Cardiology and Transplant, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada. Address reprint requests to Heather Ross, MD, FRCP(C), Toronto General Hospital, 10 NU 129, 200 Elizabeth St., Toronto, Ontario, Canada M5G 2C4. © 2004 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 36 (Suppl 2S), 504S–508S (2004)
C2, SIMULECT, AND CERTICAN IN HEART TRANSPLANTS
C2 levels correlate closely with acute rejection in liver transplantation. A prospective, open label multicenter trial conducted in 307 de novo liver transplant recipients provided an important pharmacokinetic correlation between C2 and acute rejection.11 This study showed that the incidence of rejection was inversely correlated with C2 levels and that trough CsA levels correlated poorly with graft rejection. To test whether C2 single-point monitoring could be utilized to predict freedom from rejection, a nonrandomized study was conducted in de novo liver transplant recipients.12 At 1 year post-LT, 80% of patients monitored with C2 were rejection free whereas only 60% of patients monitored with C0 were rejection free. The incidence of nephrotoxicity was similar in patients monitored with C0 or C2 levels. Correlation between the area under the concentration curve, or AUC from 0 to 4 hours, and CsA C2 levels were confirmed in a population of 35 stable adult patients ⬎1 year after liver transplantation.13 In this study CsA monitoring with a C2 range from 300 to 600 ng/mL resulted in greater clinical benefit (no rejection and no increase in serum creatinine) compared to C0 or higher C2 levels. In HT, CsA C2 levels have an excellent correlation with AUC from 0 to 4 hours whereas C0 levels have a relatively poor correlation with AUC from 0 to 4 hours.14 The results of C0 versus C2 monitoring were compared in a monitoring study of 109 stable HT patients treated with CsA. Cyclosporine monitoring was initially based on C2 levels (300 – 600 ng/mL) and thereafter monitored by C0 (100 –200 ng/mL).15 Primary endpoints assessed were clinical benefits, defined as no change in left ventricular ejection fraction, mortality or an increase in serum creatinine more than 10% compared to baseline. Greater clinical benefit was observed in 69% of patients monitored by C2 versus 43% of the patients monitored by C0 (P ⫽ .0001). This benefit was attributed mostly to a lower number of patients experiencing impairment in renal function during C2 monitoring. This study failed to show improved freedom from rejection in those patients monitored by C2 levels, which may be related to the low CsA C2 target range used. C2 levels have also demonstrated correlation with absorption profiling and clinical outcomes in stable HT recipients.16 Target C2 levels at various time-points immediately after transplant or in stable HT patients have not been clearly determined. We conducted a prospective study to determine whether C0 or C2 levels better predict clinical outcomes in de novo and stable HT patients.17 We conducted a two period prospective study with paired determinations of CsA levels at C0 and C2 in 89 patients post-HT (77 males, 12 females; mean age 56 ⫾ 11.2 years), performed during regular visits to our clinic. During period I, 116 C0 –C2 paired determinations were done in 70 patients with a follow-up of 6 months. CsA dosing was monitored and adjusted according to C0 levels with investigators blinded to C2 levels. During period II, 103 C0 –C2 paired determinations were performed in 55 patients with a follow-up of 5 months. During this period CsA dosing was
505S
monitored and adjusted according to C2 levels with investigators blinded to C0 levels. The incidence of infections, level of creatinine and calculated creatinine clearance did not differ between patients monitored by C0 or by C2. Higher C2 levels were significantly associated with absence of rejection [C2 levels, 966.5 ⫾ 469.8 ng/mL versus 764.6 ⫾ 297.1 ng/mL, no rejection versus rejection, respectively (P ⫽ .037)]. C2 levels associated with absence of biopsy proven rejection, at different time-points post-HT, were as follows: from 0 to 3 months, 1350 ⫾ 371.4 ng/mL; from 3 to 6 months, 1403 ⫾ 485.2 ng/mL; from 6 to 12 months, 1175 ⫾ 415.4 ng/mL; and from 12 to 24 months, 947.7 ⫾ 470 ng/mL. Based on theses studies, the monitoring C2 levels is clinically feasible, correlates with clinical outcomes better than C0 levels, and is associated with a reduction in rejection episodes in both de novo and stable long-term HT patients. However, further studies are needed to confirm the goal range for C2 levels at various time points after transplantation. The monitoring of neoral 2 hours absorption with simulect in heart transplantation (MOTOWN) study is a 12-month, multicenter, randomized, study designed to evaluate the benefit of C2 monitoring of cyclosporine on safety and efficacy outcomes in de novo cardiac transplant recipients receiving basiliximab induction and mycophenolate mofetil (MMF) and prednisone maintenance therapy. This study will provide important information about the role of C2 monitoring in de novo cardiac transplant patients. Target C2 levels required when cyclosporine is used in conjunction with everolimus or sirolimus in cardiac transplantation require further study. SIMULECT IN CARDIAC TRANSPLANTATION
The use of induction agents in transplantation is associated with a reduction in the incidence of early rejection and graft loss.18,19 Basiliximab (Simulect®, Novartis Pharmaceuticals Corporation) is a chimeric anti-interleukin-2 receptor monoclonal antibody proven to be safe and effective in the prophylaxis of acute renal allograft rejection.20 In this study, there were significantly fewer episodes of rejection in renal transplant recipients treated with basiliximab versus those patients receiving placebo. The survival after 1-year follow-up was similar in both groups. The safety and efficacy of basiliximab was also recently demonstrated in studies conducted in kidney and liver transplantation.21–23 A Spanish study randomized 101 adult cardiac allograft recipients to either basiliximab or OKT3 induction, with cyclosporine, MMF and steroid maintenance therapy. There was a trend toward a lower incidence of adverse events with basiliximab versus OKT3 with similar rates of rejection grade ⱖ3A (29.2% versus 25.0%, respectively).24 Given the importance of achieving suitable basiliximab blood levels for effective IL-2 receptor blockade, the dilutional effect of cardiopulmonary bypass and the potential for antibody loss in the perfusion circuit must be considered when establishing basiliximab dosing protocols and timing
506S
DELGADO AND ROSS
Fig 1. Kaplan -Meier estimates of the incidence rates of efficacy failure (biopsy-proven acute rejection of grade ⱖ3 A, acute rejection associated with HDC, death, graft loss or lost to follow-up) by treatment group.
of drug delivery in HT. Currently it is recommended that basiliximab be given within 6 to 12 hours postsurgery. Controversy exists regarding how long calcineurin inhibitor use can be delayed after HT in order to minimize renal toxicity and maximize clinical effectiveness, however cyclosporine is usually started within 2 to 4 days after transplantation.25 We conducted a study to assess the safety and efficacy of basiliximab and delayed cyclosporine initiation in patients with renal dysfunction (persistent serum creatinine ⱖ200 umol/L for at least 3 months) undergoing HT. Comparisons were done using an historical group of patients who received rabbit antithymocyte serum (RATS) as induction therapy.26 No significant differences were observed in renal function or rejection with the use of either basiliximab or RATS. Cyclosporine was initiated with a mean of 7.3 days in the basiliximab group. The mean pre-OHT creatinine was 243.28 ⫾ 48.09 umol/L, at 1 week post-OHT 180.71 ⫾ 39.79 umol/L (P ⫽ .02), at 1 month 166.43 ⫾ 57.91 umol/L (P ⫽ .019), at 3 months 182.86 ⫾ 25.82 umol/L (P ⫽ .01) and at 6 months 179 ⫾ 45.04 umol/L (P ⫽ .024). No patients required long-term dialysis. The combined use of basiliximab and delayed initiation of cyclosporine in HT recipients with chronic renal dysfunction was safe and may be a reasonable therapeutic approach to minimize renal dysfunction, however, further studies are needed to demonstrate short- and long-term efficacy of basiliximab in combination with different immunosuppressive agents.
CERTICAN™ IN HEART TRANSPLANTATION
Everolimus (Certican™, Novartis Pharmaceuticals Corporation), a derivative of rapamycin, is a macrocyclic immunosuppressive agent with unique antiproliferative activity.27,28 Everolimus binds to the FK506-binding protein and arrests the cell cycle in the G1 phase. This characteristic may allow everolimus to interact synergistically with cyclosporine. Everolimus has been shown to be safe and effective in reducing acute rejection in kidney transplant patients29,30 and to be more potent than cyclosporine in extending graft survival in animals.31 A randomized, double blind, clinical trial was conducted comparing everolimus with azathioprine in de novo HT patients.32 A total of 634 patients were randomly assigned to receive 1.5 mg of everolimus per day, 3 mg of everolimus per day, or 1 to 3 mg/kg per day of azathioprine. The primary endpoint was a composite of biopsy proven acute rejection of at least grade 3A, acute rejection associated with hemodynamic compromise, death, graft loss, or loss to follow up (Fig 1). At 6 months, significantly more patients in the azathioprine group had reached the primary efficacy endpoint than in either of the everolimus groups. Intravascular ultrasound was used to assess coronary intimal proliferation at baseline and at 12 months post-HT. The average increase in the maximal intimal thickness from baseline to 12 months was smaller in the two everolimus groups than in the azathioprine group. The incidence of vasculopathy, defined as an increase in the maximal intimal thickness of at
C2, SIMULECT, AND CERTICAN IN HEART TRANSPLANTS
least 0.5 mm from baseline in at least one matched slice, was also lower in the everolimus groups (35.7% in the 1.5 mg group; 30.4% in the 3 mg group and 52.8% in the azathioprine group). The rates of cytomegalovirus infection were significantly lower in the everolimus groups than in the azathioprine group. However, serum creatinine levels were significantly higher in the two everolimus groups than in the azathioprine group, most likely related to the potentiation of cyclosporine. Everolimus is the first immunosuppressive agent proven to be efficacious in preventing vasculopathy at 12 months post-HT. Further studies are needed to determine the optimal dose of everolimus with other concomitant agents, and to determine the long-term benefits and effectiveness of everolimus in patients with established transplant vasculopathy. The use of C2 monitoring to optimize cyclosporine exposure, especially with concomitant everolimus use in order to enhance the efficacy and safety of everolimus is planned for future studies. SUMMARY
Cyclosporine A 2-hour post-dose level (C2) monitoring is the single most sensitive sampling point for assessment of the area under the curve. Ongoing studies suggest that it is a very useful predictor of clinical outcomes in heart transplantation. The combination of basiliximab and C2 monitoring may confer further protection against acute rejection. Certainly induction therapy with delayed cyclosporine initiation may prevent renal dysfunction in patients with elevated creatinine pretransplant. Everolimus is the first immunosuppressive agent shown to reduce the development of graft vasculopathy in de novo heart transplant recipients. The major limitations to long-term survival in cardiac transplant recipients remain transplant coronary artery disease and malignancy. Rejection, though decreasing in frequency, still remains common early after transplant. The patient population undergoing transplantation has evolved over the past 10 years. Patients are more likely to be critically ill, at higher status, and ventricular assist supported. Flexibility in immunosuppressive therapies allows clinicians to adjust therapy to each individual’s potential toxicity and rejection risk. Strategies for monitoring immunosuppressive drugs to improve efficacy without increased toxicity allows further refinement. The evolution of cardiac transplantation is away from protocolized treatment. Over the next 20 years improved therapies and monitoring will allow patients to be treated individually in terms of rejection, malignancy, and transplant coronary artery disease risk. REFERENCES 1. Ross H, Hendry P, Dipchand A, et al: 2001 Canadian cardiovascular society consensus conference on cardiac transplantation. Can J Cardiol 19:620, 2003 2. Hunt SA: Current status of cardiac transplantation. JAMA 280:1692, 1998
507S 3. Ginns L, Cosimi A, Morris P: Immunosuppression in Transplantation. Massachusetts: Blackwell Science; 1999 4. Valentine H: Neoral use in the cardiac transplant recipient. Transplant Proc 32:27S, 2000 5. Kasiske BL, Heim-Duthoy K, Venkateswara R, et al: The relationship between cyclosporine pharmacokinetic parameters and subsequent acute rejection in renal transplant patients. Transplantation 46:716, 1998 6. Cole EH: Neoral monitoring: limitations of trough level monitoring and the potential role of limited sampling strategies. Transplant Proc 32:1556, 2000 7. Mahalati K, Belitzky P, Sketris I, et al: Neoral monitoring by simplified sparse sampling area under the concentration-time curve: its relationship to acute rejection and cyclosporine nephrotoxicity early after kidney transplantation. Transplantation 68:55, 1999 8. Keon 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 9. Grant D, Kneteman N, Tchervenkov J, et al: Peak cyclosporine levels (Cmax) correlated with freedom from liver graft rejection: results of a prospective, randomized comparison of neural and sandimmune for liver transplantation (NOF-8). Transplantation 67:1133, 1999 10. Mahalati K, Belitsky P, Sketris I, et al: Neoral monitoring by simplified sparse sampling area under the concentration-time curve. Transplantation 68:55, 1999 11. Levy G, Burra P, Cavallari A, et al: Improved clinical outcomes for liver transplant recipients using cyclosporine based on 2-hr post-dose levels (C2). Transplantation 73:840, 2002 12. Levy G: Relationship of pharmacokinetics to clinical outcomes. Transplant Proc 31:1654, 1999 13. Cantarovich M, Barkun J, Tchervenkov J, et al: Comparison of neoral dose monitoring with cyclosporine trough levels versus 2hr postdose levels in stable liver transplant patients. Transplantation 66:1621, 1998 14. Cantarovich M, Barkun J, Tchervenkov J, et al: Comparison of neoral dose monitoring with cyclosporine trough levels versus 2hr postdose levels in stable liver transplant patients. Transplantation 66:1621, 1998 15. Cantarovich M, Elstein E, Varennes B, et al: Clinical benefit of neural dose monitorin with cyclosporine 2-hr post-dose levels compared with trough levels in stable heart transplant patients. Transplantation 68:1839, 1999 16. 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 17. Delgado D, Rao V, Cusimano RJ, et al: Monitoring of cyclosporine 2-hr post-dose and trough levels in heart transplantation. J Heart Lung Transp 21:102, 2002 18. Carrier M, White M, Perrault LP, et al: A 10-year experience with intravenous thymoglobulin in induction of immunosuppression following heart transplantation. J Heart Lung Transplant 18:1218, 1999 19. 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 20. Kahan BD, Rajagopalan PR, Hall M: Reduction of the occurrence of acute cellular rejection among renal allograft recipients treated with basiliximab, a chimeric anti-ionterleukin-2 receptor monoclonal antibody. United States Simulect Renal Study Group. Transplantation 67:276, 1999 21. Sollinger H, Kaplan B, Pescovitz MD, et al: Basiliximab versus antithymocyte globulin for prevention of acute renal allograft rejection. Transplantation 72:1915, 2001
508S 22. Matl I, Bachleda P, Lao M, et al: Safety and efficacy of an alternative basiliximab (Simulect) regimen after renal transplantation: administration of a single mf dose on the first postoperative day in patients receiving triple therapy with azathioprine. Transpl Int 16:45, 2003 23. Lawn JG, Davies EA, Mouad G, et al: Randomized doubleblind study of immunoprophylaxis with basiliximax, a chimeric anti-interleukin-2 receptor monoclonal antibody, in combination with mycophenolate mofetil-containing triple therapy in renal transplantation. Transplantation 75:37, 2003 24. Crespo-Leiro MG, Rodriguez-Lambert JL, Segovia JL, et al: Study of the safety and tolerability of Simulect® (basiliximab) versus OKT3 in heart transplantation. J Heart Lung Transplant 22:S141, 2003 25. Kirklin JK, Young JB, McGiffin DC: Heart transplantation. New York: Churchill Livingstone; 2002 26. Delgado DH, Miriuka S, Cusimano RJ, et al: Use of basiliximab and cyclosporine in heart transplant patients with preoperative renal dysfunction. J Heart Lung Transplant (in press)
DELGADO AND ROSS 27. Schuler W, Sedrani R, Cottens S, et al: SDZ RAD, a new rapamycin derivative: pharmacological properties in vitro and in vivo. Transplantation 64:36, 1997 28. Schuurman HJ, Cottens S, Fuchs S, et al: SDZ RAD, new rapamycin derivative: synergism with cyclosporine. Transplantation 64:32, 1997 29. Neumayer HH, Paradis K, Korn A, et al: Entry-into-human study with the novel immunosuppressant SDZ RAD in stable renal transplant recipients. Br J Clin Pharmacol 48:69, 1999 30. Kahan BD, Kaplan B, Lorber MI, et al: RAD in de novo renal transplantation: comparison of three doses on the incidence and severity of acute rejection. Transplantation 71:1400, 2001 31. Nikolova Z, Hof A, Baumlin Y, et al: Efficacy of SDZ RAD compared with CsA monotherapy and combined Rad/FTY720 treatment in a murine cardiac allotransplantation model. Transpl Immunol 9:43, 2001 32. Eisen HJ, Tuzcu EM, Dorent R, et al: Everolimus for the prevention of allograft rejection and vasculopathy in cardiac transplant recipients. N Engl J Med 349:847, 2003