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Recommendations for Use of Everolimus After Heart Transplantation: Results From a Latin-American Consensus Meeting
Recommendations for Use of Everolimus After Heart Transplantation: Results From a Latin-American Consensus Meeting E.A. Bocchi, L. Ahualli, M. Amuchastegui, F. Boullon, B. Cerutti, R. Colque, D. Fernandez, A. Fiorelli, P. Olaya, N. Vulcado and S.V. Perrone ABSTRACT Despite improvements during the last decades, heart transplantation remains associated with several medical complications, which limit clinical outcomes: acute rejection with hemodynamic compromise, cytomegalovirus (CMV) infections, allograft vasculopathy, chronic renal failure, and neoplasias. Everolimus, a proliferation signal inhibitor, represents a new option for adjunctive immunosuppressive therapy. Everolimus displays better efficacy in de novo heart transplant patients than azathioprine for prophylaxis of biopsy-proven acute rejection episodes of at least ISHLT grade 3A (P ⬍ .001), of allograft vasculopathy (P ⬍ .01), and of CMV infections (P ⬍ .01). These findings suggest that everolimus potentially play an important role as part of immunosuppressive therapy in heart transplant recipients. Heart transplant investigators from Latin America produced recommendations for everolimus use in daily practice based on available data and their own experience.
H
EART TRANSPLANTATION has been established as a procedure for treatment of refractory heart failure since the early 1980s with widespread applications due to advances in patient and immunosuppressive management. However, postoperative complications, infections, and rejection episodes, side effects of immunosuppressive drugs, allograft vasculopathy, and neoplasias remain frequent events in the early and late follow-up periods after heart transplantation. Allograft vasculopathy is the primary cause of late morbidity and mortality in these recipients.1 New immunosuppressive agents have been investigated seeking to prevent or reduce these complications. Calcineurin inhibitors as well as purine biosynthesis inhibitors, azathioprine and mycophenolate mofetil (MMF), are not effective in preventing intimal thickening early after heart transplantation.2 MMF does not reduce intimal thickening during the first year after transplantation compared with azathioprine, except for lumen area.3 Also, there was no significant difference between MMF and azathioprine in quantitative coronary angiographic measurements at 3 years posttransplantation.4 Everolimus, a novel macrolide immunosuppressant agent is indicated for the prevention of organ rejection after cardiac and renal transplantation. It blocks the function of the key regulatory protein— FK-binding protein 12 rapamycin-associated protein (FRAP, mTOR)—which © 2006 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 38, 937–942 (2006)
mediates growth factor–stimulated cell proliferation, leading to cell cycle arrest in the G1 stage. Applying the results of new immunosuppressive drug trials in the clinical setting is frequently a challenge for physicians. Guidelines on the use of everolimus would be desirable to support physician decisions in clinical practice. The Latin-American Everolimus Consensus Meeting took place in June 2005, including a panel of key experts in heart transplantation from Uruguay, Colombia, Brazil, and Argentina. The participants produced recommendations about everolimus use after heart trans-
From the Institutions of the participants of the Consensus Meeting: Heart Institute (E.A.B.), Heart Failure and Heart Transplantation Unit, São Paulo, Brazil; Hospital Argerich (L.A.), Buenos Aires, Argentina; Hospital Privado de Córdoba (M.A., A.F.), Córdoba, Argentina; Hospital Francés (F.B.), Buenos Aires, Argentina; ICI (B.C.), Montevideo, Uruguay; Hospital Italiano (R.C.), Cordoba, Argentina; Clinica Cardiovascular Santa Maria (D.F.), Medellin, Colombia; Fundación Valle de Lili (P.O.), Cali, Colombia; Hospital Italiano (N.V.), Buenos Aires, Argentina; and Instituto FLENI (S.V.P.), Buenos Aires, Argentina. This consensus was sponsored by Novartis Latin America. Address reprint requests to Prof Edimar Alcides Bocchi, Rua Oscar Freire 2077 apto 161, São Paulo, Brazil CEP 05409-011. E-mail: [email protected] 0041-1345/06/$–see front matter doi:10.1016/j.transproceed.2006.02.049 937
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plantation based on clinical trial results and their own experience. PHARMACODYNAMIC PROFILE OF EVEROLIMUS
Everolimus, a proliferation signal inhibitor, exerts its immunosuppressive effects by blocking interleukin (IL)-2 and IL-15-driven hematopoietic (T- and B-) cell proliferation. In addition, it inhibits growth factor–stimulated proliferation of nonhematopoietic elements, including vascular smooth muscle cells. At the molecular level it acts by inhibiting activation of p70S6 kinase.5 Everolimus combined with cyclosporine and methylprednisolone significantly reduced T-cell proliferation.6 Synergistic activities between everolimus and cyclosporine,7 FTY 720,8 and MMF9 have been reported in animal models. Antagonism between everolimus and tacrolimus has not been demonstrated.10 In preclinical studies everolimus prevented: (1) renal chronic rejection in a rat model,11 (2) cardiac chronic rejection defined by intimal thickening in a rat model of aorta transplantation,12 (3) bronchial obliterative lesions in a porcine model of bronchial transplantation,13 (4) chronic tracheal rejection in a rat model,14 (5) atherosclerosis in transplanted carotid arteries,15 and (6) lung epithelial destruction and airway remodeling in a pig model.16 PHARMACOKINETIC PROFILE OF EVEROLIMUS
Heart transplant patients receiving everolimus 0.75 or 1.5 mg twice daily reached higher average Cmin values than the therapeutic concentration threshold (ie, 3 ng/mL) during the first 6 months after transplantation. Cmin was well correlated with the area-under-the-curve (AUC). Cmax and AUC values were dose proportional.17 It is recommended that everolimus be consistently administered either with or without food to avoid fluctuations in drug exposure over time and at the same time as cyclosporine microemulsion.18 The cytochrome P450(CYP) enzymes 3A4, 3A5, and 2C8 are involved in hepatic and gut wall metabolism of everolimus.19 Concomitant administration of CYP3A4 inducers and inhibitors alter the pharmacokinetic profile of everolimus (Table 1). Patients with hepatic impairment may show reduced everolimus clearance.20 AfricanAmerican patients may have an average of 20% lower systemic exposure to everolimus, indicating that they may need higher doses; in fact the recommended starting dose for African-Americans is 3 mg/d.21 INDICATIONS FOR EVEROLIMUS IN HEART TRANSPLANT PATIENTS BASED ON EFFICACY
A recent large, randomized, double-blind, doubledummy, prospective, multicenter trial assessed the efficacy, safety, tolerability as well as incidence of vasculopathy of two doses of everolimus (1.5 mg and 3.0 mg per day) versus azathioprine during the first 12 months after
BOCCHI, AHUALLI, AMUCHASTEGUI ET AL Table 1. Drugs Interactions With Everolimus Acting by CYP3A Inhibition or Induction or in Countertransporter P-glycoprotein5 Drug
Cyclosporine microemulsion Erythromycin Azithromycin Itraconazole Rifampicin Ketoconazole Ritonavor Rifabutin Calcium channel blockers Fluconazole Carbamazepine Phenobarbital Phenytoin
CYP3A and P-glycoproterin effect
Everolimus blood levels
1 CYP3A and P-Gly inhibitor CYP3A inhibitor CYP3A inhibitor CYP3A inducer CYP3A inhibitor CYP3A inhibitor CYP3A inducer CYP3A and P-Gly inhibitor CYP3A and P-Gly inhibitor CYP3A inducer CYP3A inducer CYP3A inducer
1 1 1 2 1 1 2 1 1 2 2 2
1, increment; 2, reduction.
heart transplantation.22 All patients received cyclosporine microemulsion and corticosteroids. Cyclosporine dose was adjusted according to trough blood levels. The average cyclosporine daily dose was 15% to 19% lower among the everolimus groups (3.5 mg/kg and 3.4 mg/kg) compared with the azathioprine group (4.2 mg/kg). Members of both everolimus groups showed: (1) a reduced incidence of biopsy-proven acute rejection of at least ISHLT grade 3A, a dose-effect relationship; (2) a smaller increase in the maximal intimal thickness and a lower incidence of vasculopathy at 12 months. Also, it has been recently reported in an abstract that this difference in efficacy was unchanged at 48 months after transplantation.23 In a single-center experience everolimus was also effective to control rejection.24 Table 2 summarizes the potential indications for everolimus taking into consideration its mechanism of action, preclinical findings, and the results of “de novo” transplantation studies. TOLERABILITY
The safety analysis revealed that the overall rate of premature discontinuation of study medication was higher among both everolimus compared with the azathioprine groups. The most common reasons for premature discontinuation related to adverse events were: renal disorders, infections, leukopenia, gastrointestinal disorders, neurological disorders, anemia, and thrombocytopenia. Mean platelet counts at 12 months were significantly lower in the 3.0 mg everolimus group compared with the other arms. Levels of triglycerides and total cholesterol were higher in both everolimus groups. Viral infections including cytomegalovirus infections
EVEROLIMUS AFTER HEART TRANSPLANTATION Table 2. Indication for Everolimus Use After de Novo Heart Transplantation in Combination with Cyclosporine and Corticosteroids Primary Prevention of rejection and allograft vasculopathy Secondary potential use In nontolerated azathioprine or mycophenolate mofetil/sodiumrelated adverse event Recurrent acute cellular rejection under adequate maintenance immunosuppression Prevention of progression of allograft vasculopathy Recurrent cytomegalovirus infection or disease with current immunosuppressive regimen (eg, mycophenolate mofetil or azathioprine)) Calcineurin inhibitor (CNI)-induced nephrotoxicity (for CNI withdrawal or substantial dose reduction) CNI severe adverse events (neuropathy with leukoencephalopathy or polyneuropathy, hemolytic-uremic syndrome) Terciary potential use In high-risk patients for cytomegalovirus infection Need for reduction of corticosteroid exposure41 To be investigated Malignancies Immunossupression for chagas’ heart disease transplantation Primary indication was considered if based on results of large trials; secondary if based in study of cases or results in subanalysis of large trials; tertiary as based in study of cases or results in subanalysis of large trials; to be investigated, based on experimental studies and hypothesis.
were less frequent but bacterial infections more frequent among everolimus cohorts compared with the azathioprine group. In renal transplantation, the rate of infections under everolimus treatment was either similar to, or lower than, that for MMF.25 Cytomegalovirus infection rate was lower among those receiving everolimus than MMF-treated patients at 12 months follow-up (P ⬍ .001). Everolimus therapy was associated with a greater increase in serum creatinine levels beginning on day 28 (P ⫽ .001 at month 3) among patients receiving full-dose cyclosporine microemulsion. Creatinine levels remained stable over time after the initial period.22 Renal impairment observed in this study was believed to be due to potentiation of cyclosporine nephrotoxicity by everolimus. Eventually renal studies confirmed that everolimus in combination with reduced cyclosporine doses resulted in good renal function.26 –28 Also, in this study the testosterone concentration increased into the normal range from baseline to month 12, a change associated with follicle-stimulatory-hormone and luteinizing hormone increments. Reactivation Chagas’ disease has been reported after heart transplantation with immunosuppressive protocols based on cyclosporine and corticosteroids associated with azathioprine or MMF.29 –34 The MMF protocol showed more reactivation compared with the azathioprine protocol. However, the reactivation did not seems to impair survival after transplantation. Apparently, there are no contrain-
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dications to everolimus in Chagas’ heart disease patients who undergo heart transplantation, but data about the safety of everolimus is Chagas’ heart disease are still not available. PRECAUTIONS WITH EVEROLIMUS PRESCRIPTION
Everolimus should be used with caution in patients with hyperlipidemia, severe hepatic impairment, or when CYP3A4 inhibitors/inducers are prescribed as comedications. Lipid-lowering therapy with pravastatin, simvastatin, atorvastatin, or fluvastatin is mandatory in everolimus-treated patients. As only pravastatin and fluvastatin are not primarily metabolized by CYP3A4 pathway, they should be considered before other statins.35 The combination of everolimus and reduced-dose cyclosporine has not been associated with an increased incidence of biopsy-proven acute rejection in a published singlecenter experience.36 Everolimus should be used with caution in patients who cannot ingest medications orally; administration must be performed via a nasogastric tube. Everolimus use is not recommended in the absence of the possibility for therapeutic drug monitoring, in cases of intolerance to proliferation signal inhibitors, among patients with severe leukocytopenia/thrombocytopenia, in recipients taking strong CYP3A4 inhibitor/inducer drugs, or during pregnancy. In patients at high risk of wound-healing concerns in the postoperative period, the risk-benefit consideration should be carefully assessed before early initiation of everolimus. However, the phase III cardiac study did not show an increase in wound-healing complications compared with azathioprine.22 Regular monitoring of white blood cell and platelet counts, cholesterol and triglyceride levels, renal function, and everolimus and cyclosporine levels should be performed in addition to the routine evaluations after heart transplantation. Reduction in everolimus dose or withdrawal should be considered when the platelet count is ⬍50,000 or WBC ⬍3,000. Endomyocardial biopsy or other method for rejection monitoring is necessary at 7 to 45 days after switching from an everolimus regimen. Everolimus has been shown to be devoid of mutagenic or clastogenic activity. It does not have oncogenic potential. Studies on everolimus use in neoplasia are ongoing. It has been reported that there is a higher incidence of neoplasias in Chagas’ disease compared with other etiologies.37 The nonmutagenic or clastogenic effect of everolimus should stimulate investigations about its potential use in heart transplantation patients as treatment of Chagas’ heart disease. DOSING RECOMMENDATIONS AND BLOOD LEVEL MONITORING OF EVEROLIMUS
Administration of everolimus should start orally in the dose of 0.75 mg twice daily as soon as possible after transplantation, with dose adjustments depending on
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BOCCHI, AHUALLI, AMUCHASTEGUI ET AL
trough blood level results. In patients with mild/moderate hepatic impairment, the initial dose should be reduced to half of the normal dose. Blood levels obtained before dose administration should be maintained between 3 ng/mL and 8 ng/mL to reduce rejection risk, achieve allograft vasculopathy protection, and obtain drug safety.27 The blood levels of everolimus should be monitored at 4 to 6 days after the first dose or at any time after everolimus dose change, or during CYP3A4 inducer/ inhibitor drug introduction/discontinuation/dose modification. Additional monitoring must be performed when hepatic function is impaired. Once steady state is reached, the monitoring schedule should be at 2-week intervals during the first 6-month follow-up; monthly until 1-year follow-up; and bimonthly thereafter. Additional monitoring is recommended when there is a suspected drug-related serious adverse event or when there is efficacy failure. HPLC/MS or FPIA are two currently available analytical methods.27,38 CYCLOSPORINE DOSING AND MONITORING DURING EVEROLIMUS PRESCRIPTION
Evaluation of the optimal dose of cyclosporine depends on the balance between rejection and safety. However, a recommended target for cyclosporine blood levels has been proposed when administered with everolimus (Table 3). Optimal C2 (2-hours after cyclosporine dose) levels are currently being evaluated in ongoing clinical trials. Experience with other combined adjunctive therapy appears promising.39,40 The guidelines for cyclosporine monitoring follow the same rules as for everolimus. Therapeutic drug monitoring must be performed anytime a CyP3A4 drug is introduced/ discontinued/dose changed and any time there is a suspicion of drug-related efficacy failure or adverse event.
Fig 1. Suggested scheme for the introduction of everolimus in maintenance after heart transplantation. CsA, cyclosporine; adjuvant therapy; mycophenolate mofetil or sodium/azathioprine.
CONCLUSIONS AND FUTURE IN IMMUNOSUPPRESSION
New immunosuppressive protocols for a reduction in heart transplant complications—infection, rejection, malignancies, nephrotoxicity, hypertension, allograft vasculopathy are gaining interest—in addition they afford a minimization of non–well-tolerated agents and a minimization or a discontinuation of steroids and calcineurin inhibitors after the early posttransplant period.24 Everolimus is a new immunosuppressive drug that reduces the incidence of rejection and allograft vasculopathy. Also, everolimus is an option as adjunctive therapy for “de novo” patients at risk for cytomegalovirus infection. Everolimus should not be used long-term with full dose of cyclosporine.
CONVERSION OF PATIENTS TO EVEROLIMUS PROTOCOL IMMUNOSUPPRESSION
Conversion of immunosuppression protocols to an everolimus regimen may be indicated when: (1) the current immunosuppression regimen shows a nontolerated adverse event, (2) efficacy failure or rejection prevention, and (3) prevention of kidney function deterioration (Figs 1 and 2). Table 3. Recommendations Concerning Target Cyclosporine Blood Levels in Heart Transplant Recipients Receiving Concomitant Everolimus* Time post-transplant (mo)
Cyclosporine serum levels (C0) (ng/mL)
0–3 3–6 ⬎6
150–175 100–150 50–100
*Factors such as balance between rejection and infection episodes, side effects, and immunological risk factors should influence the optimal dose of cyclosporine. C0 means cyclosporine blood levels immediately before the next dose.
Fig 2. Suggested scheme for the introduction of everolimus in maintenance in patients with renal failure requiring immediate cyclosporine dose reduction. CsA, cyclosporine; adjuvant therapy; mycophenolate mofetil or sodium/azathioprine; EMBx, endomyocardial biopsy; Cr, creatinine. Note: Renal function experiment requires immediate calcineurin inhibitor dose reduction.
EVEROLIMUS AFTER HEART TRANSPLANTATION
This consensus meeting provided physicians with recommendations about everolimus indications and management in de novo and maintenance heart transplant patients. Updated recommendations will be produced when data from ongoing studies comparing everolimus with MMF and evaluating other immunosuppressive regimens combining everolimus and mycophenolate sodium are available. Finally, new recommendations will benefit from a larger experience in the Latin-American population, in particular including patients with Chagas’ heart disease.
REFERENCES 1. Taylor DO, Edwards LB, Boucek MM: The Registry of the International Society for Heart and Lung Transplantation: twentyfirst official adult heart transplantation report—2004. J Heart Lung Transplant 23:796, 2004 2. Valantine H, Zuckermann A: From clinical trials to clinical practice: an overview of certican® (everolimus) in heart transplantation. J Heart Transplant 24:S185, 2005 3. Kobashigawa J, Muller L, Renlund D, et al: A randomized active-controlled trial of mycophenolate mofetil in heart transplant recipients. Transplantation 66:507, 1998 4. Eisen HJ, Kobashigawa J, Keogh A, et al: J Heart Lung Transplant 24:517, 2005 5. Chapman TM, Perry CM: Everolimus. Drugs 64:861, 2004 6. Bohler T, Waiser J, Budde K, et al: The in vivo effect of rapamicina dervate SDZ RAD on lymphocyte proliferation. Transplant Proc 30:2195, 1998 7. Schuurnan HJ, Cottens S, Fuchs S, et al: SDZ RAD, a new rapamycin derivate: synergism with cyclosporine. Transplantation 64:32, 1997 8. Nikolova Z, Hof A, Baumlin Y, et al: The peripheral lymphocyte count predicts graft survival in DA to Lewis heterotopic heart transplantation treated with FTY720 and SDZ RAD. Transpl Immunol 8:115, 2000 9. Reis A, Megahed M, Reinhard T, et al: Coadministration of the new macrolide immunosuppressive RAD and mycophenolate mofetil in experimental corneal transplantation. Transplantation 70:1397, 2000 10. Delaney MP, Higgins RM, Morris AG: FK506 and the rapamycin analogue, SDZ RAD do not have antagonistic effects on lymphocytes from renal transplant patients. (abstract). Am J Transpl 1(Suppl 1):301, 2001 11. Viklicky O, Zou H, Muller V, et al: SDZ-RAD prevents manifestations of chronic rejection in rat renal allografts. Transplantation 69:497, 2000 12. Shuurman HJ, Pally C, Weckbecker G, et al: SDZ RAD inhibits cold ischemic-induced vascular remodeling. Transplant Proc 31:1024, 1999 13. Salminen US, Alho H, Tasknen E, et al: Effects of rapamycin analogue SDZ RAD on obliterative lesions in a porcine heterotopic bronchial allograft model. Transplant Proc 30:2204, 1998 14. Weckbecker G, Caballero V, Court M, et al: Differential effects of FTY720, RAD, and CsA on signs of chronic rejection in the rat tracheal allograft model. Graft 5:145, 2002 15. Matsumoto Y, Hof A, Baumlin Y, et al: Differential effect of cyclosporin A and SDZ RAD on neointima formation of carotid allograft in apolipoprotein E-deficient mice. Transplantation 76: 1166, 2003 16. Salminen US, Maasita PK, Taskien, et al: Prevention of small airway obliteration in a suine heterotopic lung allograft model. J Heart Lung Transplant 19:193, 2000 17. Pirron U, Kovarik JM, Eisen H, et al: Longitudinal pharmacokinetics of a everolimus in de novo heart transplantation patients
941 and its influence on cyclosporine. Transplantation 74(suppl):211, 2002 18. Kovarik JM, Hartmann S, Figueiredo J, et al: Effect of food on everolimus absortion: quantification in healthy subjects and a confirmatory screening in patients with renal transplants. Pharmacotherapy 22:154, 2002 19. Jacobsen W, Serkova N, Hausen B, et al: Comparison of in vivo metabolism of the macrolide immunosuppressants sirolimus and RAD. Transplant Proc 33:514, 2001 20. Kovarik JM, Sabia HD, Figueiredo J, et al: Influence of hepatic impairment on everolimus pharmacokinetics: implications for dose adjustment. Clin Pharmacol Ther 70:423, 2001 21. Kovarik JM, Kaplan B, Silva HT, et al: Pharmacokinetics of an everolimus-cyplosporine immunosuppressive regimen over the first 6 months after kidney transplantation. Am J Transplant 3:606, 2003 22. Eisen HJ, Tuzcu M, Dorent R, et al: Everolimus for the prevention of allograft rejection and vasculopathy in cardiactransplant recipients. N Engl J Med 349:847, 2003 23. Kobashigawa J, Hare J, Eisen H, et al: Everolimus in cardiac transplantation 48 months results. Am J Transpl 2005:abstr 374 24. Zuckermann A: clinical experience with Certican© (Everolimus) in maintenance heart transplant patients at the Medical University of Vienna. J Heart Transplant 24:S206, 2005 25. Vitko S, Margreiter R, Weimar W, et al: Everolimus (Certican ®) 12-months safety and efficacy versus mycophenolate mofetil in the novo renal transplant recipients. Transplantation 78:1532, 2004 26. Vitko S, Margreiter R, Weimar W, et al: Everolimus (Certican) 12 months safety and efficacy versus mycophenolate mofetil in de novo renal transplant recipients. Transplantation 24:S206, 2005 27. Starling RC, Hare JM, Hauptan P, et al: Therapeutic drug monitoring for everolimus in heart transplantation recipients based on exposure-effect modeling. Am J Transplantation 4:2126, 2004 28. Kramer BK, Neumayer HH, Stahl R, et al: Graft function, cardiovascular risk factors, and sex hormones in renal transplant recipients on an immunosuppressive regimen of everolimus, reduced dose of cyclosporine, and basiliximab Transplant Proc 37:1601, 2005 29. Bacal F, Silva CP, Bocchi EA, et al: Mychophenolate mofetil increased Chagas’ disease reactivation in heart transplanted patients: comparison between two different protocols. Am J Transplant 5:2017, 2005 30. Bocchi EA, Bellotti G, Mocelin AO, et al: Heart transplantation for chronic Chagas’ heart disease Ann Thorac Surg 61:1727, 1996 31. Bocchi EA, Bellotti G, Uip D, et al: Long-term follow-up after heart transplantation in Chagas’ disease. Transplant Proc 25:1329, 1993 32. Bocchi EA, Fiorelli A, for the Guidelines Group: The paradox of survival results after heart transplantation for cardiomyopathy caused by Trypanosoma cruzi. First Guidelines Group for Heart Transplantation of the Brazilian Society of Cardiology. Ann Thorac Surg 71:1833, 2001 33. Bocchi EA, Fiorelli A: The Brazilian experience with heart transplantation: a multicenter report. First Guideline Group for Heart Transplantation of the Brazilian Society of Cardiology. J Heart Lung Transplant 20:637, 2001 34. Urinovsky F, Salomone O, Amuchâstegui M, et al: Morbimortalidad de los pacientes con miocardiopatia chagásica y transplante cardı´aco. Experiencia inicial. Rev Arg Cardiol 71:325, 2003 35. Kovarik JM, Hartmann S, Huber M, et al: Pharmacokinetic and pharmacodynamic assessment of HMG-CoA reductase inhibitors when coadministered with Everolimus. J Clin Pharmacology 42:222, 2002
942 36. Lehmkuhl H, Hetzer R: Clinical experience with Certican® (Everolimus) in de novo heart transplant patients at the Deutsches Herzzentrum Berlin. J Heart Lung Transplant 24:S201, 2005 37. Bocchi EA, Higuchi ML, Vieira ML, et al: Higher incidence of malignant neoplasms after heart transplantation for treatment of chronic Chagas’ heart disease. J Heart Lung Transplant 17:399, 1998 38. Boyd J, Arabshahi L, Roberts M, et al: A new FPIA immunoassay for the quantitative determination of everolimus in whole blood. Thera Drug Monit 27:213, 2005
BOCCHI, AHUALLI, AMUCHASTEGUI ET AL 39. 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 transplantation. Transplantation 68:1839, 1999 40. Delgado DH, Rao V, Cusimano RJ, et al: Monitoring of cyclosporine 2-hr post-dose and trough levels in heart transplantation. J Heart Lung Transplant 21:102, 2002 41. Eisen H, Ross H: Optimizing the immunosuppressive regimen in heart transplantation. J Heart Transplant 23(suppl):S207, 2004
H
EART TRANSPLANTATION has been established as a procedure for treatment of refractory heart failure since the early 1980s with widespread applications due to advances in patient and immunosuppressive management. However, postoperative complications, infections, and rejection episodes, side effects of immunosuppressive drugs, allograft vasculopathy, and neoplasias remain frequent events in the early and late follow-up periods after heart transplantation. Allograft vasculopathy is the primary cause of late morbidity and mortality in these recipients.1 New immunosuppressive agents have been investigated seeking to prevent or reduce these complications. Calcineurin inhibitors as well as purine biosynthesis inhibitors, azathioprine and mycophenolate mofetil (MMF), are not effective in preventing intimal thickening early after heart transplantation.2 MMF does not reduce intimal thickening during the first year after transplantation compared with azathioprine, except for lumen area.3 Also, there was no significant difference between MMF and azathioprine in quantitative coronary angiographic measurements at 3 years posttransplantation.4 Everolimus, a novel macrolide immunosuppressant agent is indicated for the prevention of organ rejection after cardiac and renal transplantation. It blocks the function of the key regulatory protein— FK-binding protein 12 rapamycin-associated protein (FRAP, mTOR)—which © 2006 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 38, 937–942 (2006)
mediates growth factor–stimulated cell proliferation, leading to cell cycle arrest in the G1 stage. Applying the results of new immunosuppressive drug trials in the clinical setting is frequently a challenge for physicians. Guidelines on the use of everolimus would be desirable to support physician decisions in clinical practice. The Latin-American Everolimus Consensus Meeting took place in June 2005, including a panel of key experts in heart transplantation from Uruguay, Colombia, Brazil, and Argentina. The participants produced recommendations about everolimus use after heart trans-
From the Institutions of the participants of the Consensus Meeting: Heart Institute (E.A.B.), Heart Failure and Heart Transplantation Unit, São Paulo, Brazil; Hospital Argerich (L.A.), Buenos Aires, Argentina; Hospital Privado de Córdoba (M.A., A.F.), Córdoba, Argentina; Hospital Francés (F.B.), Buenos Aires, Argentina; ICI (B.C.), Montevideo, Uruguay; Hospital Italiano (R.C.), Cordoba, Argentina; Clinica Cardiovascular Santa Maria (D.F.), Medellin, Colombia; Fundación Valle de Lili (P.O.), Cali, Colombia; Hospital Italiano (N.V.), Buenos Aires, Argentina; and Instituto FLENI (S.V.P.), Buenos Aires, Argentina. This consensus was sponsored by Novartis Latin America. Address reprint requests to Prof Edimar Alcides Bocchi, Rua Oscar Freire 2077 apto 161, São Paulo, Brazil CEP 05409-011. E-mail: [email protected] 0041-1345/06/$–see front matter doi:10.1016/j.transproceed.2006.02.049 937
938
plantation based on clinical trial results and their own experience. PHARMACODYNAMIC PROFILE OF EVEROLIMUS
Everolimus, a proliferation signal inhibitor, exerts its immunosuppressive effects by blocking interleukin (IL)-2 and IL-15-driven hematopoietic (T- and B-) cell proliferation. In addition, it inhibits growth factor–stimulated proliferation of nonhematopoietic elements, including vascular smooth muscle cells. At the molecular level it acts by inhibiting activation of p70S6 kinase.5 Everolimus combined with cyclosporine and methylprednisolone significantly reduced T-cell proliferation.6 Synergistic activities between everolimus and cyclosporine,7 FTY 720,8 and MMF9 have been reported in animal models. Antagonism between everolimus and tacrolimus has not been demonstrated.10 In preclinical studies everolimus prevented: (1) renal chronic rejection in a rat model,11 (2) cardiac chronic rejection defined by intimal thickening in a rat model of aorta transplantation,12 (3) bronchial obliterative lesions in a porcine model of bronchial transplantation,13 (4) chronic tracheal rejection in a rat model,14 (5) atherosclerosis in transplanted carotid arteries,15 and (6) lung epithelial destruction and airway remodeling in a pig model.16 PHARMACOKINETIC PROFILE OF EVEROLIMUS
Heart transplant patients receiving everolimus 0.75 or 1.5 mg twice daily reached higher average Cmin values than the therapeutic concentration threshold (ie, 3 ng/mL) during the first 6 months after transplantation. Cmin was well correlated with the area-under-the-curve (AUC). Cmax and AUC values were dose proportional.17 It is recommended that everolimus be consistently administered either with or without food to avoid fluctuations in drug exposure over time and at the same time as cyclosporine microemulsion.18 The cytochrome P450(CYP) enzymes 3A4, 3A5, and 2C8 are involved in hepatic and gut wall metabolism of everolimus.19 Concomitant administration of CYP3A4 inducers and inhibitors alter the pharmacokinetic profile of everolimus (Table 1). Patients with hepatic impairment may show reduced everolimus clearance.20 AfricanAmerican patients may have an average of 20% lower systemic exposure to everolimus, indicating that they may need higher doses; in fact the recommended starting dose for African-Americans is 3 mg/d.21 INDICATIONS FOR EVEROLIMUS IN HEART TRANSPLANT PATIENTS BASED ON EFFICACY
A recent large, randomized, double-blind, doubledummy, prospective, multicenter trial assessed the efficacy, safety, tolerability as well as incidence of vasculopathy of two doses of everolimus (1.5 mg and 3.0 mg per day) versus azathioprine during the first 12 months after
BOCCHI, AHUALLI, AMUCHASTEGUI ET AL Table 1. Drugs Interactions With Everolimus Acting by CYP3A Inhibition or Induction or in Countertransporter P-glycoprotein5 Drug
Cyclosporine microemulsion Erythromycin Azithromycin Itraconazole Rifampicin Ketoconazole Ritonavor Rifabutin Calcium channel blockers Fluconazole Carbamazepine Phenobarbital Phenytoin
CYP3A and P-glycoproterin effect
Everolimus blood levels
1 CYP3A and P-Gly inhibitor CYP3A inhibitor CYP3A inhibitor CYP3A inducer CYP3A inhibitor CYP3A inhibitor CYP3A inducer CYP3A and P-Gly inhibitor CYP3A and P-Gly inhibitor CYP3A inducer CYP3A inducer CYP3A inducer
1 1 1 2 1 1 2 1 1 2 2 2
1, increment; 2, reduction.
heart transplantation.22 All patients received cyclosporine microemulsion and corticosteroids. Cyclosporine dose was adjusted according to trough blood levels. The average cyclosporine daily dose was 15% to 19% lower among the everolimus groups (3.5 mg/kg and 3.4 mg/kg) compared with the azathioprine group (4.2 mg/kg). Members of both everolimus groups showed: (1) a reduced incidence of biopsy-proven acute rejection of at least ISHLT grade 3A, a dose-effect relationship; (2) a smaller increase in the maximal intimal thickness and a lower incidence of vasculopathy at 12 months. Also, it has been recently reported in an abstract that this difference in efficacy was unchanged at 48 months after transplantation.23 In a single-center experience everolimus was also effective to control rejection.24 Table 2 summarizes the potential indications for everolimus taking into consideration its mechanism of action, preclinical findings, and the results of “de novo” transplantation studies. TOLERABILITY
The safety analysis revealed that the overall rate of premature discontinuation of study medication was higher among both everolimus compared with the azathioprine groups. The most common reasons for premature discontinuation related to adverse events were: renal disorders, infections, leukopenia, gastrointestinal disorders, neurological disorders, anemia, and thrombocytopenia. Mean platelet counts at 12 months were significantly lower in the 3.0 mg everolimus group compared with the other arms. Levels of triglycerides and total cholesterol were higher in both everolimus groups. Viral infections including cytomegalovirus infections
EVEROLIMUS AFTER HEART TRANSPLANTATION Table 2. Indication for Everolimus Use After de Novo Heart Transplantation in Combination with Cyclosporine and Corticosteroids Primary Prevention of rejection and allograft vasculopathy Secondary potential use In nontolerated azathioprine or mycophenolate mofetil/sodiumrelated adverse event Recurrent acute cellular rejection under adequate maintenance immunosuppression Prevention of progression of allograft vasculopathy Recurrent cytomegalovirus infection or disease with current immunosuppressive regimen (eg, mycophenolate mofetil or azathioprine)) Calcineurin inhibitor (CNI)-induced nephrotoxicity (for CNI withdrawal or substantial dose reduction) CNI severe adverse events (neuropathy with leukoencephalopathy or polyneuropathy, hemolytic-uremic syndrome) Terciary potential use In high-risk patients for cytomegalovirus infection Need for reduction of corticosteroid exposure41 To be investigated Malignancies Immunossupression for chagas’ heart disease transplantation Primary indication was considered if based on results of large trials; secondary if based in study of cases or results in subanalysis of large trials; tertiary as based in study of cases or results in subanalysis of large trials; to be investigated, based on experimental studies and hypothesis.
were less frequent but bacterial infections more frequent among everolimus cohorts compared with the azathioprine group. In renal transplantation, the rate of infections under everolimus treatment was either similar to, or lower than, that for MMF.25 Cytomegalovirus infection rate was lower among those receiving everolimus than MMF-treated patients at 12 months follow-up (P ⬍ .001). Everolimus therapy was associated with a greater increase in serum creatinine levels beginning on day 28 (P ⫽ .001 at month 3) among patients receiving full-dose cyclosporine microemulsion. Creatinine levels remained stable over time after the initial period.22 Renal impairment observed in this study was believed to be due to potentiation of cyclosporine nephrotoxicity by everolimus. Eventually renal studies confirmed that everolimus in combination with reduced cyclosporine doses resulted in good renal function.26 –28 Also, in this study the testosterone concentration increased into the normal range from baseline to month 12, a change associated with follicle-stimulatory-hormone and luteinizing hormone increments. Reactivation Chagas’ disease has been reported after heart transplantation with immunosuppressive protocols based on cyclosporine and corticosteroids associated with azathioprine or MMF.29 –34 The MMF protocol showed more reactivation compared with the azathioprine protocol. However, the reactivation did not seems to impair survival after transplantation. Apparently, there are no contrain-
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dications to everolimus in Chagas’ heart disease patients who undergo heart transplantation, but data about the safety of everolimus is Chagas’ heart disease are still not available. PRECAUTIONS WITH EVEROLIMUS PRESCRIPTION
Everolimus should be used with caution in patients with hyperlipidemia, severe hepatic impairment, or when CYP3A4 inhibitors/inducers are prescribed as comedications. Lipid-lowering therapy with pravastatin, simvastatin, atorvastatin, or fluvastatin is mandatory in everolimus-treated patients. As only pravastatin and fluvastatin are not primarily metabolized by CYP3A4 pathway, they should be considered before other statins.35 The combination of everolimus and reduced-dose cyclosporine has not been associated with an increased incidence of biopsy-proven acute rejection in a published singlecenter experience.36 Everolimus should be used with caution in patients who cannot ingest medications orally; administration must be performed via a nasogastric tube. Everolimus use is not recommended in the absence of the possibility for therapeutic drug monitoring, in cases of intolerance to proliferation signal inhibitors, among patients with severe leukocytopenia/thrombocytopenia, in recipients taking strong CYP3A4 inhibitor/inducer drugs, or during pregnancy. In patients at high risk of wound-healing concerns in the postoperative period, the risk-benefit consideration should be carefully assessed before early initiation of everolimus. However, the phase III cardiac study did not show an increase in wound-healing complications compared with azathioprine.22 Regular monitoring of white blood cell and platelet counts, cholesterol and triglyceride levels, renal function, and everolimus and cyclosporine levels should be performed in addition to the routine evaluations after heart transplantation. Reduction in everolimus dose or withdrawal should be considered when the platelet count is ⬍50,000 or WBC ⬍3,000. Endomyocardial biopsy or other method for rejection monitoring is necessary at 7 to 45 days after switching from an everolimus regimen. Everolimus has been shown to be devoid of mutagenic or clastogenic activity. It does not have oncogenic potential. Studies on everolimus use in neoplasia are ongoing. It has been reported that there is a higher incidence of neoplasias in Chagas’ disease compared with other etiologies.37 The nonmutagenic or clastogenic effect of everolimus should stimulate investigations about its potential use in heart transplantation patients as treatment of Chagas’ heart disease. DOSING RECOMMENDATIONS AND BLOOD LEVEL MONITORING OF EVEROLIMUS
Administration of everolimus should start orally in the dose of 0.75 mg twice daily as soon as possible after transplantation, with dose adjustments depending on
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trough blood level results. In patients with mild/moderate hepatic impairment, the initial dose should be reduced to half of the normal dose. Blood levels obtained before dose administration should be maintained between 3 ng/mL and 8 ng/mL to reduce rejection risk, achieve allograft vasculopathy protection, and obtain drug safety.27 The blood levels of everolimus should be monitored at 4 to 6 days after the first dose or at any time after everolimus dose change, or during CYP3A4 inducer/ inhibitor drug introduction/discontinuation/dose modification. Additional monitoring must be performed when hepatic function is impaired. Once steady state is reached, the monitoring schedule should be at 2-week intervals during the first 6-month follow-up; monthly until 1-year follow-up; and bimonthly thereafter. Additional monitoring is recommended when there is a suspected drug-related serious adverse event or when there is efficacy failure. HPLC/MS or FPIA are two currently available analytical methods.27,38 CYCLOSPORINE DOSING AND MONITORING DURING EVEROLIMUS PRESCRIPTION
Evaluation of the optimal dose of cyclosporine depends on the balance between rejection and safety. However, a recommended target for cyclosporine blood levels has been proposed when administered with everolimus (Table 3). Optimal C2 (2-hours after cyclosporine dose) levels are currently being evaluated in ongoing clinical trials. Experience with other combined adjunctive therapy appears promising.39,40 The guidelines for cyclosporine monitoring follow the same rules as for everolimus. Therapeutic drug monitoring must be performed anytime a CyP3A4 drug is introduced/ discontinued/dose changed and any time there is a suspicion of drug-related efficacy failure or adverse event.
Fig 1. Suggested scheme for the introduction of everolimus in maintenance after heart transplantation. CsA, cyclosporine; adjuvant therapy; mycophenolate mofetil or sodium/azathioprine.
CONCLUSIONS AND FUTURE IN IMMUNOSUPPRESSION
New immunosuppressive protocols for a reduction in heart transplant complications—infection, rejection, malignancies, nephrotoxicity, hypertension, allograft vasculopathy are gaining interest—in addition they afford a minimization of non–well-tolerated agents and a minimization or a discontinuation of steroids and calcineurin inhibitors after the early posttransplant period.24 Everolimus is a new immunosuppressive drug that reduces the incidence of rejection and allograft vasculopathy. Also, everolimus is an option as adjunctive therapy for “de novo” patients at risk for cytomegalovirus infection. Everolimus should not be used long-term with full dose of cyclosporine.
CONVERSION OF PATIENTS TO EVEROLIMUS PROTOCOL IMMUNOSUPPRESSION
Conversion of immunosuppression protocols to an everolimus regimen may be indicated when: (1) the current immunosuppression regimen shows a nontolerated adverse event, (2) efficacy failure or rejection prevention, and (3) prevention of kidney function deterioration (Figs 1 and 2). Table 3. Recommendations Concerning Target Cyclosporine Blood Levels in Heart Transplant Recipients Receiving Concomitant Everolimus* Time post-transplant (mo)
Cyclosporine serum levels (C0) (ng/mL)
0–3 3–6 ⬎6
150–175 100–150 50–100
*Factors such as balance between rejection and infection episodes, side effects, and immunological risk factors should influence the optimal dose of cyclosporine. C0 means cyclosporine blood levels immediately before the next dose.
Fig 2. Suggested scheme for the introduction of everolimus in maintenance in patients with renal failure requiring immediate cyclosporine dose reduction. CsA, cyclosporine; adjuvant therapy; mycophenolate mofetil or sodium/azathioprine; EMBx, endomyocardial biopsy; Cr, creatinine. Note: Renal function experiment requires immediate calcineurin inhibitor dose reduction.
EVEROLIMUS AFTER HEART TRANSPLANTATION
This consensus meeting provided physicians with recommendations about everolimus indications and management in de novo and maintenance heart transplant patients. Updated recommendations will be produced when data from ongoing studies comparing everolimus with MMF and evaluating other immunosuppressive regimens combining everolimus and mycophenolate sodium are available. Finally, new recommendations will benefit from a larger experience in the Latin-American population, in particular including patients with Chagas’ heart disease.
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941 and its influence on cyclosporine. Transplantation 74(suppl):211, 2002 18. Kovarik JM, Hartmann S, Figueiredo J, et al: Effect of food on everolimus absortion: quantification in healthy subjects and a confirmatory screening in patients with renal transplants. Pharmacotherapy 22:154, 2002 19. Jacobsen W, Serkova N, Hausen B, et al: Comparison of in vivo metabolism of the macrolide immunosuppressants sirolimus and RAD. Transplant Proc 33:514, 2001 20. Kovarik JM, Sabia HD, Figueiredo J, et al: Influence of hepatic impairment on everolimus pharmacokinetics: implications for dose adjustment. Clin Pharmacol Ther 70:423, 2001 21. Kovarik JM, Kaplan B, Silva HT, et al: Pharmacokinetics of an everolimus-cyplosporine immunosuppressive regimen over the first 6 months after kidney transplantation. Am J Transplant 3:606, 2003 22. Eisen HJ, Tuzcu M, Dorent R, et al: Everolimus for the prevention of allograft rejection and vasculopathy in cardiactransplant recipients. N Engl J Med 349:847, 2003 23. Kobashigawa J, Hare J, Eisen H, et al: Everolimus in cardiac transplantation 48 months results. Am J Transpl 2005:abstr 374 24. Zuckermann A: clinical experience with Certican© (Everolimus) in maintenance heart transplant patients at the Medical University of Vienna. J Heart Transplant 24:S206, 2005 25. Vitko S, Margreiter R, Weimar W, et al: Everolimus (Certican ®) 12-months safety and efficacy versus mycophenolate mofetil in the novo renal transplant recipients. Transplantation 78:1532, 2004 26. Vitko S, Margreiter R, Weimar W, et al: Everolimus (Certican) 12 months safety and efficacy versus mycophenolate mofetil in de novo renal transplant recipients. Transplantation 24:S206, 2005 27. Starling RC, Hare JM, Hauptan P, et al: Therapeutic drug monitoring for everolimus in heart transplantation recipients based on exposure-effect modeling. Am J Transplantation 4:2126, 2004 28. Kramer BK, Neumayer HH, Stahl R, et al: Graft function, cardiovascular risk factors, and sex hormones in renal transplant recipients on an immunosuppressive regimen of everolimus, reduced dose of cyclosporine, and basiliximab Transplant Proc 37:1601, 2005 29. Bacal F, Silva CP, Bocchi EA, et al: Mychophenolate mofetil increased Chagas’ disease reactivation in heart transplanted patients: comparison between two different protocols. Am J Transplant 5:2017, 2005 30. Bocchi EA, Bellotti G, Mocelin AO, et al: Heart transplantation for chronic Chagas’ heart disease Ann Thorac Surg 61:1727, 1996 31. Bocchi EA, Bellotti G, Uip D, et al: Long-term follow-up after heart transplantation in Chagas’ disease. Transplant Proc 25:1329, 1993 32. Bocchi EA, Fiorelli A, for the Guidelines Group: The paradox of survival results after heart transplantation for cardiomyopathy caused by Trypanosoma cruzi. First Guidelines Group for Heart Transplantation of the Brazilian Society of Cardiology. Ann Thorac Surg 71:1833, 2001 33. Bocchi EA, Fiorelli A: The Brazilian experience with heart transplantation: a multicenter report. First Guideline Group for Heart Transplantation of the Brazilian Society of Cardiology. J Heart Lung Transplant 20:637, 2001 34. Urinovsky F, Salomone O, Amuchâstegui M, et al: Morbimortalidad de los pacientes con miocardiopatia chagásica y transplante cardı´aco. Experiencia inicial. Rev Arg Cardiol 71:325, 2003 35. Kovarik JM, Hartmann S, Huber M, et al: Pharmacokinetic and pharmacodynamic assessment of HMG-CoA reductase inhibitors when coadministered with Everolimus. J Clin Pharmacology 42:222, 2002
942 36. Lehmkuhl H, Hetzer R: Clinical experience with Certican® (Everolimus) in de novo heart transplant patients at the Deutsches Herzzentrum Berlin. J Heart Lung Transplant 24:S201, 2005 37. Bocchi EA, Higuchi ML, Vieira ML, et al: Higher incidence of malignant neoplasms after heart transplantation for treatment of chronic Chagas’ heart disease. J Heart Lung Transplant 17:399, 1998 38. Boyd J, Arabshahi L, Roberts M, et al: A new FPIA immunoassay for the quantitative determination of everolimus in whole blood. Thera Drug Monit 27:213, 2005
BOCCHI, AHUALLI, AMUCHASTEGUI ET AL 39. 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 transplantation. Transplantation 68:1839, 1999 40. Delgado DH, Rao V, Cusimano RJ, et al: Monitoring of cyclosporine 2-hr post-dose and trough levels in heart transplantation. J Heart Lung Transplant 21:102, 2002 41. Eisen H, Ross H: Optimizing the immunosuppressive regimen in heart transplantation. J Heart Transplant 23(suppl):S207, 2004