New trends in immunosuppression Focus on adequate MPA exposure in renal transplant recipients
Wolfgang Arns
Agenda:
dose → exposure (PK) → response (PD)
• The benefit of MPA exposure early and late after renal transplantation
• EC-MPS in comparison to MMF • High MPA exposure from the very early beginning • The value of MPA in maintenance therapy
Agenda
• The benefit of MPA exposure early and late after renal transplantation
• EC-MPS in comparison to MMF • High MPA exposure from the very early beginning • The value of MPA in maintenance therapy
Incidence of acute rejection at 6 months post-transplant (%)
Mycophenolate not only reduces the rate of early acute rejection… 30
24.7%
25 20
15.5%
p15% or HLA-MM ≥4 or AA
Van Gelder T, in press, post hoc analysis of FDCC
Relationship between MPA exposure and acute rejection
• Full analysis set •
MPA AUC on day 3 vs BPAR in 1st month •
•
MPA AUC on day 3 vs BPAR in 1st year •
•
p value = 0.009
p value = 0.006
MPA AUC on day 28 vs BPAR > 1st month •
p value = 0.56
key message
MPA exposure increases with time post-transplant
120
MPA AUC [μg·h/ml]
100
High target AUC ~4 g MMF equivalent
80
60
Intermediate target AUC ~2 g MMF equivalent
40
magic MPA AUC of 30
Low target AUC ~1 g MMF eqivalent*
20
0 0
20
40
60
80
100
120
140
Days post-transplant Hale MD et al. Clin Pharmacol Ther 1998;64:672–83.
*)1 g MMF is eqivalent to 720 mg EC-MPS
As MPA exposure increases with a delay over time, intensified early dosing regimen could be the solution
120
MPA AUC [μg·h/ml]
100
High target AUC ~4 g MMF equivalent 80
60
Intermediate target AUC ~2 g MMF equvalent
40
“magic” AUC Low target AUC ~1 g MMF equivalent
20
0 0
20
40
60
80
100
120
Days post-transplant Hale MD et al. Clin Pharmacol Ther 1998;64:672–83.
140
Optimyze Study • Open-label, prospective, randomized, parallel group pilot study • 3 centers in Germany • Phase 1 Objectives: feasibility to achieve target MPA-AUC (> 40 g*h/mL) and safety of an intensified EC-MPS regimen in 75 patients • Phase 2 Objectives: therapeutic benefit of this regimen in 128 patients Glander P, Sommerer C, Arns W et al, CJASN 2010; 5(4): 503-511 Sommerer C, Glander P, Arns W et al, Transplantation 2011; 91(7): 779-85
Study Design
Intensified
2880 2160 1440 mg / day EC-MPS CsA + Steroids + Basiliximab
Randomization 1:1 1440 mg / day EC-MPS CsA + Steroids + Basiliximab
Standard
0
14
6 months study period
42
180 days
Study Endpoint • Primary efficacy endpoint
Composite of biopsy proven acute rejection (BPAR), graft loss and death at Month 6
• Key safety endpoints Incidences of anemia, leucopenia, gastrointestinal side effects and infections
Mean Daily EC-MPS Dose CsA Dose 3500
mg/d 2880
3000
Standard
Intensified
Day 1-14
6.7 ±1.6
6.4 ± 1.7
Day 15-42
4.4 ± 1.9
4.2 ± 1.9
Day 43-180
3.0 ± 1.2
3.1 ±1.1
2500
2160 2000
1440
1500 1000 500 0 Day 1-14
Day 15- 42
Day 43-180
Standard Intensified
Dosing regimens were applied according to the protocol
MPA-AUC Standard Proposed upper therapeutic exposure (30 mg*h/L)
Target exposure level (40 mg*h/L)
Proposed lower therapeutic exposure (30 mg*h/L)
Almost all patients of the intensified group reached the target MPA-AUC of 30 to 60 µg*h/mL
Intensified
IMPDH Activity Standard
Intensified
The intensified regimen led to a significantly stronger inhibition of IMPDH post transplantation
Efficacy Endpoint
p=0.017
20
n=11
Patients (%)
Intensified
17
15
10
5
n=3 n=2 3
n=1 2
Death
5
n=2
n=2
33
3
Graft Loss
Standard
BPAR
Efficacy Endpoint: BPAR Grading
Standard
Intensified
Total
n=65
n=63
n=128
BANFF IA
7 (10.8%)
1 (1.6%)
8 (6.5%)
BANFF IB
2 (3.1%)
0
2 (1.6%)
BANFF IIA
1 (1.5%)
0
1 (0.8%)
BANFF IIB
1 (1.5%)
1 (1.6%)
1 (0.8%)
Number of biopsies
62
47
109
Patients with biopsies
37
29
66
BANFF Klassifikation n (%)
12 months data
IMPDHAEC (µmol*s-1*mol-1) *h
What´s about TDM of MPA exposure: PK-PD-modeling MPA-AUC vs IMPDH-AEC
MPA-AUC mg*h/L
IMPDH activity µmol*s-1*mol-1
What´s about TDM of MPA exposure: PK-PD-modeling single MPA vs single IMPDH 150
125
EC50 1.24 to 1.76 μg/mL
100
75
E= (Emax*C)/(EC50+C) 50
Above a certain threshold increased MPA exposure leads not to more IMPDH suppression.
25
EC-MPS has the potential for a longer exposure.
0
5
10
15
20
25
30
35
40
45
50
MPA-concentration [µg/mL]
No difference was found in calculated EC50 values during the first 3 weeks day 3: 1.24 mg/L [95% CI: 0.59-1.89]; day 10: 1.76 mg/L [95% CI: 1.06-2.97] day 21: 1.44 mg/L [95% CI: 0.89-2.0]).
Need for more data from larger cohorts to validate the safety and efficacy of this concept • prospectively defined fixed effect meta analysis model • Two 6 month, randomized, parallel group, open label, multicenter studies with almost identical design Intensified EC-MPS
2880 mg/d 2160 mg/d
n=213
1440 mg/d EC-MPS CsA + Steroids +/- anti-IL2R induction
Randomization at kidney Tx
Standard EC-MPS
n=219
1440 mg/d EC-MPS CsA + Steroids +/- anti-IL2R induction
Day 0
Day 14
Day 42
CsA; cyclosporine; EC-MPS: enteric-coated mycophenolate sodium; RTx: renal transplant
Day 180 42
EC-MPS dosing • The mean daily EC-MPS doses showed close adherence to the planned regimens in both groups 3500 2763
Mean (SD) (mg/day)
3000
Safety population 2122
2500 2000
1982
1399 1411
1456
1389
1354
1369
1500
1359
1326 1276
1252 1260
1000 500 0 1-14
15-28
EC-MPS: enteric-coated mycophenolate sodium
29-42
43-56
57-84
Days (post-transplantation)
85-120
121-180
43
MPA exposure (AUC0-12h) • Median MPA exposure was ~33-47% higher in the Intensified EC-MPS dose group in the first 6-weeks post-transplant • 80.5% achieved target MPA-AUC by Day 3 in Intensified group PK population
50.8 42.9
44.3
42.7
43.8
42.5
44.3
39.8 33.5 30.9
36.3
28.7
AUC: Area under the curve at steady state
44
Primary efficacy endpoint: Treatment failure • 5% (p=ns) less treatment failure (BPAR, graft loss or death at Month 6) in Intensified group • significantly lower (5.5%) BPAR rates in Intensified group p=0.11
Percentage of patients
22.4% 19.3% 17.4% 13.8%
15
10
p=0.034
ITT population
25
20
Intensified Standard
n=38 n=50
n=30 n=43
5
n=5
2.3%
n=8 3.6%
n=3 n=3 1.4% 1.3%
0 Treatment failure
BPAR*
Graft Loss*
Death*
Study endpoints * Components of treatment failure
45
IMPDH based mycophenolate dosing MPA predose
N=52
IMPDH inhibition
N=52
ns
Criticism: Only 720 mg/day EC-MPS dosing with either TAC or CSA!
Raggi MC et al, Transplantation 2010; 90(12): 1536-41
If fixed dose is the right answer: Does one size fits all? The role of body weight in the Singapore experience.
12 mg/kg BW → AUC 45 mg·h/L
Yau W-P et al, NDT 2007; 22,:3638-3645
The value of MPA predose TDM revisited @ 1 month
@ 1 year
Miura M et al, TDM 2011; 33: 295-302
Conclusion
• The introduction of mycophenolate has improved transplant outcome in short and longterm use. • Dose reduction in mycophenolate therapy is associated with lower outcome. In comparison to MMF: EC-MPS is bioeqivalent in equimolar dosing, but has superior tolerability that allows higher dosing with increased MPA exposure. • High exposure of MPA from the very early beginning at transplantation has a great impact on transplant outcome. EC-MPS gives the opportunity for safe intensified dosing strategy according to the optimyze concept.
Agenda
• The benefit of MPA exposure early and late after renal transplantation
• EC-MPS in comparison to MMF • High MPA exposure from the very early beginning • The value of MPA in maintenance therapy „MPA based immunosuppression“
Design of the ZEUS study Month 0 – 4.5
Anti IL-2R + Cyclosporine + EC-MPS + CS
Month 4.5
Stepwise conversion (2 weeks)
Cyclosporine + EC-MPS + CS CsA trough level 100-150 ng/ml
Everolimus + EC-MPS + CS Everolimus trough level 6-10 ng/ml
After Month 12, patients were included in an observational follow up.
Anti IL-2R = Basiliximab, EC-MPS = Enteric-Coated Mycophenolate Sodium, CS = Corticosteroids
Renal Function Adjusted Values (Group (LS-)Means from ANCOVA model, 95% CI) 80
Everolimus N=154
< 0.0001
0.0002
< 0.0001
+6.5 [3.1, 10.0]
70
+7.8 ml/min (ml / min)
GFR Nankivell
GFR Slope ml/min
< 0.0001
60
-1.1 [-4.8, 2.5] Cyclosporin N=146
ITT Population
50
40 Rando.
M6
M9
M12
M24
Renal function maintains over a period of 24 month
Renal Function Adjusted Values (Group (LS-)Means from ANCOVA model, 95% CI)
80
Everolimus< 0.0001
< 0.0001
< 0.0001
GFR Slope ml/min
< 0.0001
+9.0 [4.4, 13.6] 70 (ml / min)
GFR Nankivell
N=154
60
+10.4 ml/min -1.5 [-6.5, 3.6]
Cyclosporin N=146
Per Protocol Population
50
40 Rando.
M6
M9
M12
M24
Renal function maintains over a period of 24 month
The influence of de novo HLA antibodies: Patients on risk – enhancing immunosuppression 100 neg/neg (550) 89%
90 pos/pos (86)
p1g/day
-20 primary non-responders (lack of efficacy, new onset of proteinuria) -10 secondary non-responders (side effects)
In the second year post transplantation about 40% of all transplanted patients are on PSI-based therapy – they will have a clear long term benefit for better renal function.
Overview: de novo immunosuppression immunological status
1.TP/PRAact ≤10% ¹)
low risk
Basiliximab Prednison Cyclosporine Mycophenolate
>1TP u./o. PRAact ≥10%
medium risk
Thymoglobuline Prednison Tacrolimus Mycophenolate
¹) PRAmax≥10% → XM+ → ATG induction
PRAact ≥80%
high risk
Plasma Exchange Rituximab Prednison Tacrolimus Mycophenolate