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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

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

Miha Arnol

University Medical Centre Ljubljana

Department of Nephrology

Centre for Kidney Transplantation

Ljubljana, Slovenia

introduction graft loss in renal transplant recipients

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.

introduction current trends in immunosuppression
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

introduction the impact of mpa dose
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.

poor adherence to the mmf regimen increased risk of graft loss
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.

enteric coated mp s formulation
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.

mpa exposure auc is similar with ec mp s or mmf
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.

conversion from mmf to ec mp s
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.

ec mp s is associated with fewer dose reductions or drug discontinuations
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.

ec mp s is associated with higher mean mpa dose
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.

conversion from mmf to ec mp s11
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.

ec mp s no compromise on safety after conversion from mmf
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.

conversion from mmf to ec mps may be associated with improvement in gi symptoms
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.

conversion from mmf to ec mps may be associated with improvement in gi symptoms14
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.

conversion from mmf to ec mp s15
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.

an increase in mpa dose after conversion from mmf to ec mps is possible
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.

slide17

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.

conversion from mmf to ec mp s18
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.

a retrospective study showed ec mp s is associated with a lower incidence of bpar than mmf
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.

additional benefits of ec mpa s
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.

slide21
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.

additional benefits of ec mp s
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.

similar efficacy in ec mp s treated patients randomised to low or standard exposure tacrolimus
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.

slide24
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.

renal function improved after early conversion to everolimus ec mp s compared to cni continuation
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.

conclusions
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.