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Enteric-Coated Mycophenolate Sodium (EC-MPS) in Renal Transplantation

Enteric-Coated Mycophenolate Sodium (EC-MPS) in Renal Transplantation. Miha Arnol. University Medical Centre Ljubljana Department of Nephrology Centre for Kidney Transplantation Ljubljana, Slovenia. 45. 35. Graft loss (%). 25. 15. 5. acute rejection. IF/TA. other.

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Enteric-Coated Mycophenolate Sodium (EC-MPS) in Renal Transplantation

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  1. Enteric-Coated Mycophenolate Sodium (EC-MPS) in Renal Transplantation Miha Arnol University Medical Centre Ljubljana Department of Nephrology Centre for Kidney Transplantation Ljubljana, Slovenia

  2. 45 35 Graft loss (%) 25 15 5 acute rejection IF/TA other recurrent disease vascular technical death with function non-compliance IntroductionGraft loss in renal transplant recipients hyperacute rejection Seron D, et al. NDT 2008; 23: 2467.

  3. IntroductionCurrent trends in immunosuppression Acute Post-Transplant Immunosuppression Maintenance Immunosuppression Optimal (dual / triple) Immunosuppression Increased allograft / patient survival Reduced toxicity CNI / Steroid minimization / withdrawal mTOR inhibitors Induction Triple IS Optimal MPA dose

  4. IntroductionThe impact of MPA dose • MMF is effective in improving graft survival. • However, GI complications may lead to dose reductions or discontinuation of therapy. • Reduced MMF dose results in reduced MPA exposure, leading to reduced efficacy. • This, in turn, may have a negative impact on graft survival. Bunnapradist S et al. Transplantation 2006; 82: 102. Le Meur Y et al. Am J Transplant 2007; 7: 2496.

  5. Poor adherence to the MMF regimen Increased risk of graft loss RETROSPECTIVE REGISTRY ANALYSIS (USRDS / MEDICARE) OF PATIENTS UNDERGOING FIRST KIDNEY TRANSPLANTATION DURING 1995–2002,RECEIVING MMF AND A CNI DURING YEAR 1 POST-TRANSPLANT Hazard ratio for graft loss p<0.001 p=0.015 p=0.09 MMFdose reduction MMFdiscontinuation Poor adherenceto MMF regimen n=7062 Takemoto SK et al. Am J Transplant 2007; 7: 2704.

  6. Enteric-coated MPS formulation EC-MPS is a formulation of MPA that… Delays release until the small intestine (pH > 5.0) Gives a similar exposure to MPA as MMF Arns W et al. Clin Transplant 2005; 19: 199.

  7. MPA exposure (AUC) is similar with EC-MPS or MMF RANDOMISED, CROSSOVER, SINGLE-DOSE STUDY IN 24 STABLE RENAL TRANSPLANT PATIENTS Arns W et al. Clin Transplant 2005; 19: 199.

  8. Conversion from MMF to EC-MPS Conversion from MMF to EC-MPSin de novo and maintenance kidney transplant patients… Can lead to a lower incidence of BPAR1 Results in fewer dose reductions and discontinuations1 Allows an increase in MPA dose3,4 Is well tolerated2,3 1. Sollinger H et al. Transplantation 2010; 89: 446. 2. Budde K et al. Am J Transplant 2004; 4: 237. 3. Shehata M et al. Transpl Int 2009; 22: 821. 4. Ortega F et al. Am J Transplant 2009; 9 (Suppl 2): 408, abs 749.

  9. EC-MPS is associated with fewer dose reductions or drug discontinuations 1709 PATIENTS (2000–2006) FROM A SINGLE CENTRE Percentages based on 2-year Kaplan-Meier estimates; p values based on log-rank test Sollinger H et al. Transplantation 2010; 89: 446.

  10. EC-MPS is associated with higher mean MPA dose 1709 consecutive renal transplant patients (2000–2006) from a single centre 1709 PATIENTS (2000–2006) FROM A SINGLE CENTRE MMF (n=1111) 1300 p=0.0004 p=0.0001 p=0.0305 EC-MPS (n=598) 1257 1250 1232 1189 1200 Mean equimolar-adjusted MPA dose (mg) 1174 1150 1136 1108 1100 1050 6 months 1 year 2 years Time following initiation of MPA therapy EC-MPS, enteric-coated mycophenolate sodium; MPA, mycophenolic acid; MMF, mycophenolate mofetil Sollinger H et al. Transplantation 2010; 89: 446.

  11. Conversion from MMF to EC-MPS Conversion from MMF to EC-MPSin de novo and maintenance kidney transplant patients… Can lead to a lower incidence of BPAR1 Results in fewer dose reductions and discontinuations1 Allows an increase in MPA dose3,4 Is well tolerated2,3 1. Sollinger H et al. Transplantation 2010; 89: 446. 2. Budde K et al. Am J Transplant 2004; 4: 237. 3. Shehata M et al. Transpl Int 2009; 22: 821. 4. Ortega F et al. Am J Transplant 2009; 9 (Suppl 2): 408, abs 749.

  12. EC-MPS: no compromise on safety after conversion from MMF MULTICENTRE, RANDOMISED, DOUBLE-BLIND STUDY TRIAL IN MAINTENANCE KIDNEY TRANSPLANT PATIENTS (B302) p=ns 100 93.7 92.6 MMF (n=163) 80 EC-MPS (n=159) p=ns 58.9 58.5 60 Incidence of event at12 months (%) p=ns 40 29.5 29.5 20 0 Any adverse event Any infection Drug-related adverse event Budde K et al. Am J Transplant 2004; 4: 237.

  13. Conversion from MMF to EC-MPS may be associated with improvement in GI symptoms MMF (n=61) EC-MPS (n=68) MULTICENTRE, RANDOMISED, OPEN-LABEL TRIAL IN KIDNEY TRANSPLANT PATIENTS EXPERIENCING GI SIDE EFFECTS WITH MMF Abdominalpain Constipation Indigestion Diarrhea Reflux Total Patients (%) Mean change in GSRS score Statistically non-significant improvement at 12 weeks in GSRS scores Improvement at 12 weeks in OTE scale for GI symptoms OTE, Overall Treatment Effect; GSRS, Gastrointestinal Symptom Rating Scale Shehata M et al. Transpl Int 2009: 22; 821.

  14. Conversion from MMF to EC-MPS may be associated with improvement in GI symptoms Improvement Arnol M et al. Assessment of GI symptoms after conversion form MMF to EC-MPS in renal Tx.

  15. Conversion from MMF to EC-MPS Conversion from MMF to EC-MPSin de novo and maintenance kidney transplant patients… Can lead to a lower incidence of BPAR1 Results in fewer dose reductions and discontinuations1 Allows an increase in MPA dose3,4 Is well tolerated2,3 1. Sollinger H et al. Transplantation 2010; 89: 446. 2. Budde K et al. Am J Transplant 2004; 4: 237. 3. Shehata M et al. Transpl Int 2009; 22: 821. 4. Ortega F et al. Am J Transplant 2009; 9 (Suppl 2): 408, abs 749.

  16. An increase in MPA dose after conversion from MMF to EC-MPS is possible MULTICENTRE, RANDOMISED, OPEN-LABEL TRIAL IN KIDNEY TRANSPLANT PATIENTS EXPERIENCING GI SIDE EFFECTS WITH MMF MMF (n=61) EC-MPS (n=68) p<0.001 Patients (%) Proportion of patients at week 12 maintained on a dose ≥1 step higher than at baseline Shehata M et al. Transpl Int 2009: 22; 821.

  17. In patients experiencing GI complaints with MMF, EC-MPS allows optimal MPA dosing without increasing GI-related complications MULTICENTRE, RANDOMISED, OPEN-LABEL, 12-WEEK TRIAL (myVIDA) Patients previously on MMF who had reported GI adverse events were randomized to either: EC-MPS (n=70) Equimolar dose 0–2 weeks dose optimization ≤720 mg bid 2–6 weeks maintenance 6–12 weeks or MMF (n=64) Same dose adjustment 50 50 p=ns p=0.0004 40.6 40 40 35.6 34.3 30 30 Patients (%) on low doses<1000 mg/day Patients (%) withGI adverse events 20 20 10.3 10 10 0 0 Ortega F et al. Am J Transplant 2009; 9 (Suppl 2): 408, abs 749.

  18. Conversion from MMF to EC-MPS Conversion from MMF to EC-MPSin de novo and maintenance kidney transplant patients… Can lead to a lower incidence of BPAR1 Results in fewer dose reductions and discontinuations1 Allows an increase in MPA dose3,4 Is well tolerated2,3 1. Sollinger H et al. Transplantation 2010; 89: 446. 2. Budde K et al. Am J Transplant 2004; 4: 237. 3. Shehata M et al. Transpl Int 2009; 22: 821. 4. Ortega F et al. Am J Transplant 2009; 9 (Suppl 2): 408, abs 749.

  19. A retrospective study showed EC-MPS is associated with a lower incidence of BPAR than MMF 1709 PATIENTS (2000–2006) FROM A SINGLE CENTRE ns p=0.0212 p=0.0004 100 86.4 84.4 MMF (n=1111) 80 EC-MPA (n=598) 60 Patients (%) 40 31.0 30.2 24.7 21.9 20 0 Graft survival BPAR Acute kidneyrejection Percentages based on 2-year Kaplan-Meier estimatesp values based on a log-rank test Sollinger H et al. Transplantation 2010; 89: 446.

  20. Additional benefits of EC-MPAS Specific kidney transplant patient populations could benefit particularly fromEC-MPS EC-MPS can be used in CNI minimisation /withdrawal protocols2,3 PPI’s do not decrease MPA exposure with EC-MPS1 1. Rupprecht K et al. J Clin Pharmacol 2009; 49: 1196. 2. Andres A et al. Transpl Int 2007; 20 (Suppl 2): 217, abs P507. 3. Budde K et al. Am J Transplant 2009; 9 (Suppl 2): 259, abs 237.

  21. MPA plasma concentration is not influenced by concomitant PPI and EC-MPS treatment in healthy volunteers 2 crossover studies in healthy volunteers: Study 1, MMF 1000 mg + pantoprazole vs MMF (n=12); Study 2, EC-MPS 720 mg + pantoprazole vs EC-MPS (n=12) - 27%* - 57%* MPA AUC 12 h (µg/µl*h) MPA Cmax 12 h (µg/µl*h) MMF MMF EC-MPS EC-MPS MMF / PPI MMF / PPI EC-MPS/ PPI EC-MPS/ PPI *p < 0.05 PPI, proton pump inhibitor; MPA, mycophenolic acid; MMF, mycophenolate mofetil; EC-MPS, enteric-coated mycophenolate sodium; AUC, area under the concentration-time curve; Cmax, maximum concentration Rupprecht K et al. J Clin Pharmacol 2009; 49: 1196.

  22. Additional benefits of EC-MPS Specific kidney transplant patient populations could benefit particularly fromEC-MPS EC-MPS can be used in CNI minimisation /withdrawal protocols2,3 PPI’s do not decrease MPA exposure with EC-MPS1 1. Rupprecht K et al. J Clin Pharmacol 2009; 49: 1196. 2. Andres A et al. Transpl Int 2007; 20 (Suppl 2): 217, abs P507. 3. Budde K et al. Am J Transplant 2009; 9 (Suppl 2): 259, abs 237.

  23. Similar efficacy in EC-MPS treated patients randomised to low- or standard-exposure tacrolimus MULTICENTRE, RANDOMISED, OPEN-LABEL TRIAL IN DE NOVO KIDNEY TRANSPLANT PATIENTS (A2409) Andres A et al. Transpl Int 2007; 20 (Suppl 2): 217, abs P507.

  24. In EC-MPS treated patients in whom tacrolimus target levels are met, renal function is better with low-exposure tacrolimus MULTICENTRE, RANDOMISED, OPEN-LABEL TRIAL IN DE NOVO KIDNEY TRANSPLANT PATIENTS (A2409) ITT population Observed cases Tacrolimus C0on target Estimated GFR (mL/min/1.73m2) p=0.326 p=0.079 p=0.038 n=145 n=137 n=117 n=111 n=85 n=69 Low Standard Low Standard Low Standard Andres A et al. Transpl Int 2007; 20 (Suppl 2): 217, abs P507.

  25. Renal function improved after early conversion to everolimus/ EC-MPS compared to CNI continuation Calculated GFR (mL/min/1.73m2) 12 months post-conversion p<0.0001 n=145 n=155 CsA + EC-MPS + corticosteroids Everolimus 1.5 mg/day + EC-MPS +CsA elimination + corticosteroids Budde K et al. Am J Transplant 2009; 9 (Suppl 2): 259, abs 237.

  26. Conclusions • GI complications associated with MMF may lead to dose reductions or discontinuation of therapy. • EC-MPS is a formulation of MPA that gives a similar exposure to MPA as MMF. • Conversion from MMF to EC-MPS in de novo and maintenance kidney transplantation can offer benefits to patients in terms of tolerability and efficacy. • There is no interaction between EC-MPS and PPI’s. • Flexibility of drug regimens with EC-MPS can allow CNI reduction or elimination.

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