SOT5_Pharmacotherapy_55 (1).pptx

Solid Organ Transplantatio n Pharmacother apy Yasar Tasnif, PharmD, BCPS, FAST Associate Professor of Practice | UTEP School of Pharmacy Transplant Case HPI: JG is a 55-year-old Hispanic male, 5’6” and 81kg. He is on the transplant waitlist for a kidney. Today, the local organ procurement agency n...

Solid Organ Transplantatio n Pharmacother apy Yasar Tasnif, PharmD, BCPS, FAST Associate Professor of Practice | UTEP School of Pharmacy Transplant Case HPI: JG is a 55-year-old Hispanic male, 5’6” and 81kg. He is on the transplant waitlist for a kidney. Today, the local organ procurement agency notifies the transplant team of a potential kidney donor. The donor is a 19 y/o, otherwise healthy male, who died in a car crash. He had no significant medical history (e.g., kidney or cardiovascular disease). The donor died in the area, and the kidney will have a minimal cold ischemia time since it is being procured locally. The crossmatch is negative, and JG has a PRA of 25%. The transplant surgeon and nephrologist reviewed the case and evaluated the recipient and donor. Based on the information given, they accept the organ for JG. Based on JG’s PRA, they determine him to be of moderate immunological risk. PMH: JG has a history of type 2 diabetes mellitus (currently controlled with a pre-transplant A1C of 5.9%) and end-stage renal disease. He is receiving 3x weekly hemodialysis. SH: Non-contributory. Transplant Case Transplant Case • What induction regimen would you choose for this patient? • Anti-thymocyte Globulin (Rabbit) + methylprednisolone • Basiliximab + methylprednisolone • Methylprednisolone alone • What maintenance regimen would you choose for this patient? • Tacrolimus + Mycophenolate + Prednisone (taper to 5mg at day 28) • Tacrolimus + Azathioprine + Prednisone (taper to 5mg at day 28) • Tacrolimus + Sirolimus + Prednisone at 0.5mg/kg to start and taper to 5mg at end of year 1 Objectives • Review the data that has led to current trends in immunosuppression therapy • Identify effective means in induction and maintenance therapy to reduce rejection and increase survival Measures of Success in Transplant Trials • Patient survival • Graft survival • Acute rejection • Biopsy proven/confirmed acute rejection (BPAR; BCAR) • Treatment failure General Approach to Immunosuppression • • • • • • • CNI, calcineurin inhibitor CSA, cyclosporine IL2RA, interleukin-2 receptor antagonist MPA, mycophenolic acid RATG, rabbit antithymocyte immunoglobulin SRL, sirolimus TAC, tacrolimus Schonder KS, Johnson HJ. Chapter 70. Solid-Organ Transplantation. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach, 9e New York, NY: McGraw-Hill; 2014. Induction Pharmacotherapy Immunosuppressants • There are 2 types of immunosuppressants: • Induction drugs: Powerful anti-rejection medicine used at or around the time of transplant surgery • Maintenance drugs: Anti-rejection medications used for the long term • “Think of a real estate mortgage; the down payment is like the induction drug and the monthly payments are like maintenance drugs. If the down payment is good enough you can lower the monthly payments, the same as for immunosuppression.” https://www.kidney.org/atoz/content/immuno Induction • Induction often signifies the use of antibody therapy. • May refer to the use of higher doses of Methylprednisolone. • Antibody induction is considered when there is a need to delay the introduction of the calcineurin inhibitors or decrease the need for steroid use. • Induction with antibody therapy is not universal for all solid organ transplants. https://www.ajmc.com/journals/supplement/2015/ace022_jan15_organtransplant_ce/ ace022_jan15_enderby?p=1 Induction • Antibody induction therapy in solid organ transplantation ranges from lowest use in liver transplant recipients (31.1%) to highest use in pancreas recipients (90.4%). • This wide range shows the variation in the use of antibody induction among the different organs and transplant centers • May be due to variability in outcomes in trials • Induction agents such as Anti-Thymocyte Globulin and Alemtuzumab profoundly deplete T-Cells • The potential benefits are lowering of acute rejection episodes and steroid minimization • Increased risk of developing infections and https://www.ajmc.com/journals/supplement/2015/ace022_jan15_organtransplant_ce/ ace022_jan15_enderby?p=1 Basiliximab vs. Placebo • A double-blind, placebo-controlled phase III study was performed to assess whether basiliximab reduced the incidence of acute rejection episodes in renal allograft recipients. • During the first 12 months, 94 (54%) basiliximab-treated patients experienced serious adverse events, compared with 106 (61%) who received placebo. Basiliximab (n=173) Placebo (n=173) P Value Rejection (1-year f/u) 35.3% 49.1% 0.009 Patient Survival (1 year) 97.1% 96% Kahan BD et al. Transplantation. 1999 Jan 27;67(2):276-84. Graft Survival (1 94.6% 93.0% NS NS Comparison of Induction Agents • There are few comparisons of antibody • • • • • induction therapy allowing early glucocorticoid withdrawal in renal-transplant recipients. Hanaway et al conducted a prospective randomized trial to compare induction therapy involving alemtuzumab vs. basiliximab vs rabbit antithymocyte globulin. Patients were stratified according to acute rejection risk High risk: Repeat transplant, panel-reactive antibodies (PRA) of 20% or more, or black race. Primary end-point: (BCAR) Secondary end-points: Efficacy Failure (composite of freedom from biopsy-confirmed Hanaway et al. N Engl J Med. 2011 May 19;364(20):1909-19. Comparison of Induction Agents • High-risk patients received: • Alemtuzumab (30mg x 1) • Or Antithymocyte globulin (Total of 1.5mg/kg daily x 4 days) • Low-risk patients received: • Alemtuzumab (30mg x 1) • Or basiliximab (20mg x 2 on days 0 and 4) • Maintenance: • All patients received tacrolimus and mycophenolate mofetil and underwent a 5-day glucocorticoid taper in a regimen of early steroid withdrawal. Hanaway et al. N Engl J Med. 2011 May 19;364(20):1909-19. BCAR, According to Risk of Graft Rejection 1 year: 3% vs. 20% (P<0.001) 1 year: 10% vs 13% (P = 0.53) Efficacy Failure 76% vs 70% (P = 0.42) 85% vs 76% (P = 0.04) Survival of Patients and Grafts NS Hanaway et al. N Engl J Med. 2011 May 19;364(20):1909-19. NS Comparison of Induction Agents • The apparent superiority of alemtuzumab in this trial with respect to early biopsy-confirmed acute rejection was restricted to patients at low risk for transplant rejection • Among high-risk patients, alemtuzumab and rabbit antithymocyte globulin had similar efficacy. Hanaway et al. N Engl J Med. 2011 May 19;364(20):1909-19. Maintenance Pharmacotherapy CNIs • The introduction of the CNIs significantly improved the outcomes of solid-organ transplantation in terms of patient and graft survival, with 1-year graft survival improving from 75% to 87% for cadaveric grafts. • The microemulsion formulation of cyclosporine has demonstrated equivalent or superior efficacy in kidney, liver, and heart transplantation recipients. • Studies comparing tacrolimus with either formulation of cyclosporine as primary immunosuppression demonstrate equivalent efficacy between the two agents in all transplantation situations. Schonder KS, Johnson HJ. Chapter 70. Solid-Organ Transplantation. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach, 9e New York, NY: McGraw-Hill; 2014. CNIs • Monotherapy with CNIs has been described. The avoidance of long-term corticosteroids is the primary advantage of CNI monotherapy, whereas the primary disadvantage is the higher incidence of rejection. • As a result, CNIs are rarely used as monotherapy. Schonder KS, Johnson HJ. Chapter 70. Solid-Organ Transplantation. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach, 9e New York, NY: McGraw-Hill; 2014. Cyclosporine vs. Azathioprine • Overall actuarial survival rates of 1000 liver transplant patients treated with cyclosporine-steroid therapy in comparison with overall actual survival rates of 170 patients treated with azathioprine-steroid therapy Iwatsuki et. al. Transplant Proc 1988; 20(Suppl 1): 498 Cyclosporine vs. Tacrolimus • Panel A – Kaplan-Meier estimates of patients with acute rejection in the tacrolimus and cyclosporine groups • Panel B – Patients requiring muromonab-CD3 for corticosteroid-resistant The U.S. Multicenter FK506 Liver Study Group. N Engl J Med rejection in the tacrolimus 1994; 331(17): 1110-5 and cyclosporine groups Cyclosporine vs. Tacrolimus • Panel A – Kaplan-Meier estimates of patient survival in the Tacrolimus and Cyclosporine Groups • Panel B – Graft survival in the Tacrolimus and Cyclosporine Groups The U.S. Multicenter FK506 Liver Study Group. N Engl J Med 1994; 331(17): 1110-5 Cyclosporine vs. Tacrolimus – 5-year survival FK506 CSA • Patient Survival Rates – Kaplan-Meier estimates of 5year patient (liver transplant) survival rates by treatment group FK506 CSA • Graft Survival Rates – Kaplan-Meier estimates of 5year graft survival rates by treatment group Wiesner. Transplantation 1998; 66(4): 493-499 Conversion from Cyclosporine to Tacrolimus at First Rejection • Estimated rate of kidney transplant patients remaining free from biopsy-proven recurrent rejection • Tacrolimus group 89.1% (95% confidence interval 79.9% – 98.6%) • Cyclosporine group, 61.4% (95% confidence interval 45.4% – 77.3%) [P=0.0021] Recurrent Rejection Withdrawals Converted to Tacrolimus (n=57) Continued Cyclosporine (n=44) 8.8 % 34.1 % 16% 50% Briggs et. al. Transplantation. 2003; 75(12): 2058-63 Azathioprine vs. Mycophenolate Mofetil AZA MMF 2 Gm MMF 3 Gm • All treatment failures, including biopsy-proven rejection • AZA 100-150 mg (n=166); MMF 2 g (n=173); MMF 3 g (n=164) The Tricontinental Mycophenolate Mofetil Renal Transplantation Study Group. Transplantation. 1996; 61(7): 1029-1037 Sirolimus vs. Azathioprine • Kidney transplant – Delay to first biopsy-confirmed acute rejection episodes in the two sirolimus groups compared with the azathioprine group (p=0·042 and p<0·001, respectively). Kahan et. al. Lancet. 2000; 356(9225): 194-202 Sirolimus vs. Azathioprine • Survival of grafts and patients in first 12 months after kidney transplantation • Allograft survival p=0·593; survival of patients p=0·625 Kahan et. al. Lancet. 2000; 356(9225): 194-202 General Target Trough Levels (Whole Blood) Day Cyclosporine (ng/mL) Tacrolimus (ng/mL) Sirolimus (ng/mL) 1 – 90 200 – 250 5 – 15 6 – 15 91 – 180 150 – 200 5 – 15 6 – 15 181 – 360 120 – 150 5 – 15 6 – 15 Corticosteroids • Corticosteroids became a part of the immunosuppressive regimens used in the first human transplantations and continue to be used today. • Their efficacy is irrefutable based on the decades of clinical experience. • Studies of corticosteroid-free immunosuppressive agent combinations with more specific immunosuppressants and induction agents suggest that corticosteroids may in the future have less of a role in maintenance immunosuppression. Schonder KS, Johnson HJ. Chapter 70. Solid-Organ Transplantation. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach, 9e New York, NY: McGraw-Hill; 2014. Steroid Free Regimens • Rajab et. al. – Steroid-free maintenance immunosuppressive protocol in kidney transplant recipients • Similar rates of patient and graft survival, with lower incidence of rejection, and weight gain • However, more patients in steroid free group required therapy for anemia (p < 0.001) Steroid Free Comparator (n= P value (n=301) 502) One-year patient survival 93.1 % 95.2 % NS One-year death censored graft survival rate 98.1 % 95.2 % NS Biopsy proven acute rejection 4.9 % 9.4 % P < 0.01 Graft loss due to rejection 0.7 % 1.8 % P < 0.05 gain 8.1 % 11 % P < 0.05 •Weight Steroid Free Group – Induction with thymoglobulin, sirolimus, Neoral and prednisone taper over five days • Comparator – Basiliximab on days 0 and 4, Cellcept 2 g/day, Neoral, and prednisone started at 2 mg/kg and tapered to 0.2 mg/kg at one month and 0.1 mg/kg at one year Rajab et. al. Clin Transplant. 2006; 20(5): 537-46 CNI – Sparing Strategies • CNI minimization and/or CNI withdrawal • Weir et. al. – 118 renal transplant recipients • CNI dose reduced or discontinued with either the addition or continuation of MMF and low-dose steroids Fig 2 – Slopes showing loss of renal function over time using the least square mean. Solid Line – no CNI; dashed line – cyclosporine; dotted line – tacrolimus. • 72.2% of the CNI withdrawal patients, 54.4% of reduced-dose CSA group, and 40% of the reduced-dose tacrolimus group had improved the slope of decay of renal function or lack of deterioration Weir et. al. Kidney Int. 2001; 59(4): 1567-73 CNI – Avoidance • Complete avoidance of CNI • Vincenti et. al. – 98 renal transplant patients were enrolled in a CNI avoidance study • Immunosuppression – Daclizumab x 5 doses, MMF 3 gm/day for the first 6 months and 2 gm thereafter, with conventional corticosteroid therapy • Primary efficacy endpoint was biopsy-proven rejection during the first 6 months post-transplant, which showed a higher rate of rejection compared to a similar regimen but with a CNI Biopsy Proven Rejection Vincenti Ekberg 6 months 48 % 26.2 % 12 Months 53 % 27.5 % a Range of time to first biopsy proven rejection: 6 days to 306 days. Graft loss due to rejection was 2%. Rejection rates with daclizumab, MMF, steroids and cyclosporine (target trough level 150–300 ng/mL from baseline through to month 4 and 100–200 ng/mL thereafter) a Ekberg et. al. Am J Transplant. 2007; 7(3): 560-70 Vincenti et. al. Transplantation. 2001; 71(9): 1282-7 Alemtuzumab Induction • Ciancio et. al. – Randomized 3 arm trial with 30 patients in each arm • Groups A (Thymoglobulin) and C (daclizumab) – Targeted trough level of tacrolimus was between 8 and 10 ng/mL, with a targeted mycophenolate dose of 1 g twice daily • Group B (Campath) – Target tacrolimus trough level was 4 to 7 ng/mL to reduce long-term nephrotoxicity, with 500 mg twice-daily doses of mycophenolate, without steroid maintenance • 80% of the patients in group B remained steroid-free 1 year postoperatively, with lower tacrolimus trough levels, no difference in infection rates, and no difference in other adverse events Thymoglobulin – Group A Campath – Group B Daclizumab – Group C P Value Death (1 Year) 6.6 % 0 10 % NS Graft Failure (1 Year) 3.3 % 0 0 NS 16.6 % 16.6 % 16.6 % NS Acute Rejection (1 Year) Caincio et. al. Transplantation. 2005; 80(4): 457-65 Transplant Case • What induction regimen would you choose for this patient? • Anti-thymocyte Globulin (Rabbit) + methylprednisolone • Basiliximab + methylprednisolone • Methylprednisolone alone • What maintenance regimen would you choose for this patient? • Tacrolimus + Mycophenolate + Prednisone (taper to 5mg at day 28) • Tacrolimus + Azathioprine + Prednisone (taper to 5mg at day 28) • Tacrolimus + Sirolimus + Prednisone at 0.5mg/kg to start and taper to 5mg at end of year 1 Transplant Case - Answers • What induction regimen would you choose for this patient? • The crossmatch is negative. Minimal cold ischemia time. The donor is a good match for the recipient. But the recipient has a PRA of 25% (moderate immunological risk). • Anti-thymocyte Globulin (Rabbit) + methylprednisolone • Benefits are lowering of acute rejection episodes and steroid minimization • The patient is diabetic; steroids increase BG. • What maintenance regimen would you choose for this patient? • Tacrolimus + Mycophenolate + Prednisone (taper to 5mg at day 28) • CNIs are the mainstay of maintenance immunosuppression Question s • Please contact me at: [email protected] u