cn-1 everolimus renal safety and efficacy extrapolations, dose recommendations lawrence hunsicker,...
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CN-1
EverolimusRenal Safety and
Efficacy Extrapolations,Dose Recommendations
Lawrence Hunsicker, MD
Professor of Medicine and Medical Director of Organ Transplantation
Carver College of Medicine at the University of Iowa
CN-2
Overview
Use of everolimus, together with cyclosporine (CsA) in usual doses, is associated with a significant reduction in kidney function
This effect is closely related to the trough (C0) levels of CsA, but unrelated to the levels of everolimus
Use of everolimus with reduced dose CsA results in calculated creatinine clearance similar to those seen in patients treated with full dose CsA and either AZA or MMF
PK/PD analyses demonstrate everolimus and CsA, at reduced dose after the first month, is effective in preventing cardiac rejection
CN-3
Certican® Proposed Dosage and Administration
Everolimus should be used in an initial dose of 1.5 mg per day in 2 divided doses, but dose adjusted to achieve a target trough level of 3 to 8 ng/mL
Recommended target exposure of CsA in thefirst month is 250 to 400 ng/mL
Exposure to CsA beyond Month 1 should be about
– 175 ng/mL for month 2 - 3
– 135 ng/mL for month 4 - 6
– 100 ng/mL beyond month 6
CN-4
Outline
Review of renal safety data from heart study B253
Role of everolimus and CsA
– PK/PD relationships for renal function Efficacy of reduced-dose CsA in cardiac
transplantation
– PK/PD efficacy heart study B253 Conclusions about safety and efficacy Dosing recommendations
CN-5Mean Creatinine Clearance (Cockcroft-Gault) Over Time—24 MonthsStudy B253
0
20
40
60
80
100
Time, months
Cre
atin
ine
clea
ran
ce (
mL
/min
)
AZAEverolimus 1.5 mgEverolimus 3.0 mg
AZA, nEverolimus 1.5 mg, nEverolimus 3.0 mg, n
122116100
205194206
152140132
Data from PTT 10.3-1b 24 months
BL 12 24
201193190
1
166169153
3
167156152
6
*
**
**** * *
*P < 0.001Error bars = Standard deviation.
CN-6
Renal Function—12 monthsStudy B253
Everolimus
AZA 1.5 mg 3.0 mgn = 145 n = 132 n = 129
Creatinine clearance mean (SD) (mL/min)
65.0 (22.89)
51.7 (19.06)*
51.3 (27.65)*
n = 149 n = 137 n = 131
Creatinine mean (SD) (mg/dL)
1.67 (0.55)
2.06 (0.67)*
2.14 (0.95)*
*P < 0.005 vs AZA
CS-20
CN-7
Outline
Review of renal safety data from heart study B253
Role of everolimus and CsA
– PK/PD relationships for renal function Efficacy of reduced-dose CsA in cardiac
transplantation
– PK/PD efficacy heart study B253 Conclusions about safety and efficacy Dosing recommendations
CN-8Absence of Renal Toxicity of Everolimus MonotherapyStudy 2201—Rheumatoid Arthritis
209-1
Parameter (mean)Placebon = 60
Everolimus 6.0 mgn = 61
Creatinine (mg/dL)
Baseline 0.78 0.78
Week 12 0.81 0.77
Week 24 0.72 0.68
Slide set CPOs.ppt s32
CN-9
Design of Kidney Transplant Studies Studies B201, B251, A2306, A2307
≤ 48 hrs
Everolimus 1.5 mg (B201: n = 194; B251: n = 193)
Everolimus 3.0 mg (B201: n = 198; B251: n = 194)
MMF 2 g (B201: n = 196; B251: n = 196)
101-2
≤ 24 hrsEverolimus 1.5 mg/d (2306: n = 112; 2307: n = 117)
Everolimus 3.0 mg/d (2306: n = 125; 2307: n = 139)
Wk 1 - 4Baseline Week 5 - 12 Month 4 - 12
B201, B251
A2306, A2307a
a With IL-2R monoclonal antibody.
n’s from CSRs
(Standard CsA)
(Reduced CsA)
CN-10
a With IL-2R monoclonal antibody.
Mean CsA Trough Levels and Creatinine Clearance With Conventional or Reduced-Dose CsA Studies B201, B251, A2306, A2307a—ITT 12-month Analysis
B201 B251 A2306 A2307CsA trough levels (ng/mL)
6 months
Everolimus 1.5 mg 173 178 82 64Everolimus 3.0 mg 158 175 83 68MMF 2 g 170 178 — —
12 months
Everolimus 1.5 mg 144 140 61 60Everolimus 3.0 mg 156 121 71 58MMF 2 g 157 167 — —
Creatinine clearance (mL/min)
Everolimus 1.5 mg 52 59 65 67Everolimus 3.0 mg 47 55 64 64MMF 2 g 54 69 — —
CN-11Heart Study B253—Creatinine Clearance Decrease 30% After Month 1 by CsA and Everolimus Concentrationa
0
20
40
60
80
100
Pat
ien
ts (
%)
< 4 4 - 6 6 - 9 ≥ 9
≤ 180
180 - 230
230 - 280≥ 280
Everolimus exposure (ng/mL)CsA exposure
(ng/m
L)
a Time-weighted average trough until event or censoring.
265-3 DV - AC B253 PKPD draft2.doc
CN-12
Outline
Review of renal safety data from heart study B253
Role of everolimus and CsA
– PK/PD relationships for renal function Efficacy of reduced-dose CsA in cardiac
transplantation
– PK/PD efficacy heart study B253 Conclusions about safety and efficacy Dosing recommendations
CN-13BPAR ISHLT Grade ≥ 3A Rates vs Everolimus ExposureStudy B253
46 44
33
19 22 1924 21
15 16
0
20
40
60
80
100
AZAª < 3 3 - 4 4 - 5 5 - 6 6 - 7 7 - 8 8 - 9 9 - 10 > 10Everolimus trough levels, ng/mL
Pa
tie
nts
wit
h B
PA
R ≥
3A
, %
104-6
BPAR rates by average everolimus trough levelto event or day 450
a At 12 months.
CN-14Percent of Patients Free of BPAR ISHLT Grade ≥ 3A Based on Everolimus Exposure Study B253—Day 1 to 225
Log-rank: Mean exposure < 3 ng/mL is statistically differentLog-rank: Mean exposure < 3 ng/mL is statistically differentfrom 3 to 8 or > 8 ng/mL (from 3 to 8 or > 8 ng/mL (PP < 0.001). < 0.001).
104-9
Everolimus trough levels≥ 8 ng/mL3 - 8 ng/mL< 3 ng/mLAZA
Time after transplantation (days)0 25 50 75 100 125 150 175 200 225
0
20
40
60
80
100
Pat
ien
ts f
ree
of
acu
te r
ejec
tio
n,
%
CN-15BPAR ISHLT Grade ≥ 3A Acute Rejection by CsA and Everolimus Concentrationa
Study B253—Days 15 - 225
0
20
40
60
80
100
Fre
qu
ency
of
BP
AR
(%
)
< 3 3 - 6 6 - 9 ≥ 9
≤ 180180 - 220
220 - 270≥ 270
Everolimus exposure (ng/mL) CsA exposure (n
g/mL)
a Time-weighted average trough until event or censoring.
265-4 DV - AC B253 PKPD draft2.doc
CN-16Rejection by CsA Exposure QuartileDay 1 to Month 1Study B253
0
10
20
30
40
BP
AR
≥ IS
HL
T 3
A (
%)
0-25 26-50 51-75 76-100
Novartis Briefing Book Table 4-11
Quartiles based on CsA exposure
1.5 mg
AZA
3.0 mg
CN-17Rejection by CsA Exposure QuartileMonths 2 to 3Study B253
0
10
20
30
40
BP
AR
≥ IS
HL
T 3
A (
%)
0-25 26-50 51-75 76-100
Novartis Briefing Book Table 4-11
Quartiles based on CsA exposure
1.5 mg
AZA
3.0 mg
CN-18Rejection by CsA Exposure QuartileMonths 4 to 6Study B253
0
10
20
30
40
BP
AR
≥ IS
HL
T 3
A (
%)
0-25 26-50 51-75 76-100
Quartiles based on CsA exposure
1.5 mg
AZA
3.0 mg
Novartis Briefing Book Table 4-12
CN-19Rejection by CsA Exposure QuartileMonths 7 to 12Study B253
0
10
20
30
40
BP
AR
≥ IS
HL
T 3
A (
%)
0-25 26-50 51-75 76-100
Quartiles based on CsA exposure
1.5 mg
AZA
3.0 mg
Novartis Briefing Book Table 4-13
CN-20Rejection by CsA Exposure QuartileEverolimus 1.5 mg Over Months 2 to 12Study B253
2.3
9.1
3.0
9.14.3
0.0
7.0
0.0
12.1
4.5
17.4
5.9
0
10
20
30
40
50
Months 2 to 3 Months 4 to 6 Months 7 to 12
Quartiles
BP
AR
≥ IS
HL
T 3
A (
%)
Quartile 1Quartile 2Quartile 3Quartile 4
225-1 ac_ci12_rev.rtf
151 126 95232 270 354 186 229 294 149 192 244Median CsAtrough levels(ng/mL)
Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4
CN-21
Outline
Review of renal safety data from heart study B253
Role of everolimus and CsA
– PK/PD relationships for renal function Efficacy of reduced-dose CsA in cardiac
transplantation
– PK/PD efficacy heart study B253 Conclusions about safety and efficacy Dosing recommendations
CN-22
Summary
The combination of everolimus with standard dose CsA is associated with reduced renal function compared with CsA with AZA or MMF
But reduced dose CsA with either dose of everolimus is associated with excellent renal outcomes, similar to those with CsA and either AZA or MMF
The use of everolimus with lower doses of CsA after month 1 is equally effective in preventing cardiac rejection
CN-23
Conclusions
Renal toxicity is primarily associated with blood levels of CsA
Antirejection efficacy is primarily associated with blood levels of everolimus
It is possible to dose these agents so as to avoid renal toxicity and maintain antirejection efficacy
Thus in the hands of transplant experts, use of everolimus as we have recommended is effective in cardiac transplantation and is safe with respect to the effects on the kidneys
CN-24
Outline
Review of renal safety data from heart study B253
Role of everolimus and CsA
– PK/PD relationships for renal function Efficacy of reduced-dose CsA in cardiac
transplantation
– PK/PD efficacy heart study B253 Conclusions about safety and efficacy Dosing recommendations
CN-25
Dose Recommendation for Everolimus
Initial dose of everolimus is 1.5 mg/day We recommend use of everolimus to achieve
trough concentrations of 3 to 8 ng/mL for the entire posttransplant period
As implied above, therapeutic monitoring of everolimus levels is appropriate
CN-26
Dose Recommendation for CsA
Recommended target exposure of CsA in thefirst month is 250 to 400 ng/mL
Exposure to CsA beyond Month 1 should approximate the median of the lowest exposure quartiles observed over time for study B253
– 175 ng/mL for month 2 - 3
– 135 ng/mL for month 4 - 6
– 100 ng/mL beyond month 6
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