Intruduction PSI MODE OF ACTION AND PHARMACOKINETICS

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1 Multidisciplinary Insights on Clinical Guidance for the Use of Proliferation Signal Inhibitors in Heart Transplantation Andreas Zuckermann, MD et al. Department of Cardio-Thoracic Surgery, Medical University of Vienna, Vienna, Austria; Intruduction Proliferation signal or mammalian targetof-rapamycin inhibitors (PSI/mTOR inhibitors) : sirolimus and everolimus new options for the prevention of acute rejection in heart transplant recipients and inhibition of cardiac allograft vasculopathy, consistent with dose-dependent reduction of intimal thickening in pre-clinical models. The Journal of Heart and Lung Transplantation February 2008 PSI MODE OF ACTION AND PHARMACOKINETICS Calcineurin inhibitors (CNIs) : cyclosporine (CsA) and tacrolimus Anti-metabolites: mycophenolate mofetil (MMF) and azathioprine (Aza) Sirolimus is a macrocyclic lactone produced by Streptomyces hygroscopicus. mab, monoclonal antibody; MHC, major histocompatibility complex; TCR, T-cell antigen receptor; MAP, mitogen-activated protein; IKK, Ikinase; NFAT, nuclear factor of activated T cells; AP-1, activated protein 1; NF-B, nuclear factor B; PI-3, phosphatidylinositol 3-phosphate; mtor, mammalian target of rapamycin; PSI, proliferation signal inhibitor; MMF, mycophenolate mofetil. everolimus having an increased oral bioavailability 1

2 EFFICACY OF PSI/mTOR INHIBITORS IN HEART TRANSPLANTATION In a randomized, open-label study of 136 de novo heart transplant recipients, sirolimus approximately halved the number of patients experiencing acute rejection within the first 6 months. Keogh A, Richardson M, Circulation 2004 In 634 de novo heart transplant recipients Eisen HJ, Tuzcu EM,. N Engl J Med 2003 with full dose CsA After one year, efficacy failure everolimus 1.5 mg/day 41.6% ( p 0.02 vs Aza), everolimus 3.0 mg/day 32.2% ( p vs Aza) Aza mg/day 52.8% Efficacy failure :death, graft loss, loss to follow-up, biopsy-proven acute rejection [BPAR] ISHLT Grade 3A, or rejection associated with hemodynamic compromise RENAL FUNCTION Everolimus and low-dose tacrolimus, with preliminary data suggesting improvement of long-term renal function after substantial CNI reduction. Chronic renal failure (CRF): Chronic renal failure is common after cardiac transplantation Mortality 5-year risk of chronic renal failure was 6.9% in heart lung transplant recipients. Heart transplant without renal transplant 36months F/u Chronic renal failure:16.5% Dialysis + renal transplant: 30% Ojo AO, N Engl J Med % to 10% of heart transplant recipients develop CNI induced endstage renal failure Myers BD, N Engl J Med Myers BD J Am Soc Nephrol 1991 From renal transplantation experience, although PSI/mTOR inhibitors do not have inherent nephrotoxicity, they may potentiate CNI-induced nephrotoxicity. A single-center, retrospective analysis Maintenance heart transplant recipient with CRF Conversion to everolimus 1.CNI exposure 2.Renal function and adequate immunosuppression. Fuchs U, Transplant Int 2005 In maintenance heart transplant recipients, receiving everolimus, target CsA trough blood levels of 50 to 80 ng/ml could prevent acute rejection Lehmkuhl H, Transplant Proc

3 Study in heart and lung recipients : Severe renal impairment (Avg. Cr: 3.25+/-1.43 mg/dl) 3 months posttransplant confirmed that sirolimus use allowed for a significant reduction in CsA dose, and resulted in improved renal function for 15 of 20 patients. Snell GI, J Heart Lung Transplant 2002 It is controversial as to whether PSI/mTOR inhibitors allow for complete CNI withdrawal without increased risk of acute rejection or chronic graft loss and with significant improvement in renal function 14 maintenance heart transplant recipients with renal impairment (Cr:3.7+/-1.2 mg/dl) CNI withdrawal & sirolimus use 1 year later 12/14 improved renal function Lyster H, Transplant Proc maintenance heart transplant recipients post-conversion 9 months later further critical evaluation of the timing of CNI withdrawal? 1. improved renal function (Cr:2.1+/ /-0.4) 2. recovery from other CNIrelated adverse events Rothenburger M, Transplantation 2006 Early CNI withdrawal coupled with conversion to sirolimus has been reported Vazquez de Prada JA, Transplant Int 2006 But the safety of early CNI withdrawal? Wyeth Pharmaceuticals; CNI use may be essential to maintain adequate immunosuppression during the first year post-transplant especially in heart transplant patients Opelz G, Am J Transplant 2003 Opelz G, Lancet 1993 OTHER ADVERSE EVENTS ASSOCIATED WITH PSI/mTOR INHIBITORS Hyperlipidemia Wound-healing complications Edema Proteinuria Infections Skin disorders Pneumonitis Wound-healing Complications A trial in de novo heart transplant recipients (6 months post-transplant f/u) abnormal healing pleural effusion sirolimus 14.7% (3.0 mg) 38.2% (3mg) 45.6%(5mg) Aza 4.7% (P=0.045) Keogh A,Circulation

4 povidone iodine instillations. No study has directly compared the wound healing complication of two drugs Any observed difference may reflect dosing protocols in clinical studies: ex first dose of everolimus was delayed until 72 hours, but sirolimus was given immediately post-transplant and a loading dose was common. The benefit > wound healing problem? Proteinuria Proteinuria, a key predictor of chronic renal failure, has been reported after conversion to PSI/mTOR inhibitors in renal transplant recipients. Proteinuria more pronounced increase in proteinuria in patients with a high pre-conversion proteinuria. In 49 maintenance heart transplant recipients Aliabadi AZ, Transplantation 2006 Severe proteinuria (1.0 mg/dl) Pre-conversion 11% After sirolimus conversion 22% (P=0.0552) Currently, there are no data on the potential of everolimus to induce proteinuria in heart transplant recipients (as to this is not routinely measured ) The cause of PSI-induced proteinuria is unknown. But evidence suggests reduced tubular re-absorption of protein PSI increase in renal blood flow that reveals previously masked proteinuria in those with CNI-related focal segmental glomerulosclerosis. CLINICAL GUIDANCE ON THE USE OF EVEROLIMUS Above literatures reviews by experienced transplant cardiologists, cardiac surgeons and nephrologists. And they suggest 4

5 Patient Selection Perspectives of Transplant Cardiologists The benefit of PSI Reducing cardiac allograft vasculopathy (CAV) anti-cancer effect of PSI/mTOR inhibitors on post-transplant malignancies (data from renal transplantation) Beneficial in patients with a history of malignancy patients at high immunologic risk, such as those with a positive crossmatch In cases of severe renal dysfunction (e.g., serum creatinine >2.0 to 2.3 mg/dl), conversion to PSI/mTOR inhibitors and CNI withdrawal does not improve renal function. Everolimus trough blood levels of 3 to 8 ng/ml ensure optimal immunosuppressive efficacy Trough blood levels of >12 ng/ml have not been evaluated Starling RC, Am J Transplant 2004 When initiating everolimus soon after transplantation, these levels are usually achieved within 1 to 2 weeks. Any everolimus dose adjustments should be based on blood trough levels obtained 4 to 5 days after the previous dosing change Once everolimus trough blood levels are within this therapeutic range CNI exposure should be reduced (by approximately 50%) C0: 50~80 ng/ml or C2: 300 ng/ml in maintenance phase 5

6 everolimus may allow delayed CsA initiation by 5 to 7 days post-transplant in patients with pre-operative renal dysfunction in order to limit CNI nephrotoxicity early post-transplant. Two issues are needed to stidy The use of everolimus in CNI free regimens? Higher everolimus trough blood levels? How to Minimize Wound-healing Complications With PSI Perspectives of a Cardiac Surgeon main focus of surgical techniques to minimize wound healing complication Using non-absorbable sutures, Delaying removal of skin sutures until 14 to 21 days posttransplant If wound-healing complications occur immediate use of aggressive surgical therapy, with possible use of vacuum-assisted closure systems During the tissue regeneration phase of wound healing (3 to 5 days posttransplant), especially in obese or diabetic patients Avoiding PSI In patients with an increased risk of wound-healing issues, such as those with LVADs: the time of initiate PSI? delayed until the increased risk has subsided Minimizing or reducing their use through aggressive steroid weaning within the first 6 months to 1 year post-transplant may be beneficial to wound. For patients who require general surgery: withdraw the PSI approximately 1 week prior to surgery and re-initiate therapy with PSI/mTOR inhibitors 14 to 21 days post-surgery, Which Parameters of Renal Function to Measure Perspectives of a Transplant Nephrologist Monitoring renal function in heart transplant recipients receiving CNIs is particularly important. Serum creatinine levels Calculated glomerular filtration rate (reliable within the range of 30 to 70 ml/min, and it is not as reliable at lower values) Measured GFR should be routinely monitored Proteinuria be monitored before making the decision to convert to PSI and at regular intervals after conversion 6

7 Thank you for your attention! 7