Kinetics and Dynamics of Immunosuppressive Drugs in Renal Transplantation

1
Kinetics and Dynamics of Immunosuppressive Drugs
in Renal Transplantation Robert Schmouder, MD,
MPH Novartis Pharmaceuticals Corporation Transplan
tation Business Unit Clinical Pharmacology
2
End Stage Renal Disease US Incident Rate
1,500
n
o
i
t
la
1,200
u
p
o
900
p
n
Rate / million population
600
illio
m
/
e
300
t
a
R

s
0
r
80
81
82
83
84
85
86
87
88
89
90
91
92
93
94
95
96
97
98
99
00
Ba
U S Renal Data System (USRDS). 2002
3
Introduction to US Kidney Transplantation

• First renal transplant in Boston, 1954
• 1954-2002 160,000 kidney transplants
• In 2002
• 104,000 with ESRD
• 54,000 on waiting kidney waiting list
• 14,600 renal transplants
• 270 transplant centers

United Network for Organ Sharing (UNOS), 2003
4
Immunosuppressive Therapy in Renal Transplantation

• Cornerstone of renal transplantation is
  multi-drug immunosuppressive regimens
• 1960-1970 steroids and azathioprine
• 1970-1980 polyclonal anti-lymphocyte antibody
• 1980 calcineurine inhibitor (cyclosporine)
• 1990 mycophenolic acid
• 1995 mTOR inhibitor
• 2000 FTY720
• Current standard of care
• steroid
• calcineurine inhibitor
• mycophenolic acid

5
Classes of Renal Transplant Drugs

• Calcineurin inhibitors
• cyclosporine
• tacrolimus
• ISATX247
• IMPDH inhibitors
• mycophenolate mofetil
• enteric coated mycophenolate sodium
• mTOR inhibitors
• sirolimus (rapamycin)
• everolimus (RAD001)
• syphingosine-1-phosphate agonists
• FTY720

6
Calcineurin Inhibitors
Cyclosporine
Tacrolimus
ISATX247
?
?
Cyclic polypeptide(11 AAs) produced by Beauveria
nivea .
Macrolide produced by Streptomyces tsukubaensis
7
Calcineurin Inhibition Signalling Pathway
8
Cyclosporine Pharmacokinetics
1400
1200
1000
800
Cyclosporine (ng/mL)
600
400
200
0
0
2
4
6
8
10
12
Hours Post Dose
From Levy G. BioDrugs. 200115279-290.
9
Blood Cyclosporine Levels vs Calcineurin
Phosphatase Activity and Intracellular IL-2
Calcineurin Inhibition in Leukocytes1
100
80
60
40
20
0
0
1
2
4
Time Point (hours)
Calcineurin immunosuppression is maximal at C2
1. Halloran PF et al. Transplantation.
1999681356-1361. 2. Sindhi R et al.
Transplantation. 200069432-436.
10
Blood Tacrolimus Levels and Calcineurin
PhosphataseActivity Early after Renal
Transplantation
Koefoed-Nielsen et al. Am J of Transplant 2002
2 173178
11
Allogeneic Mixed Lymphocyte Reaction (rat)
Cyclosporine Tacrolimus
? ?
IL-2 Activity (U/mL)
0.001
0.01
0.1
1
10
100
1000
Concentration (nM)
12
ISATX247 Calcineurin Inhibition
Aspeslet et al. Txp Proc. 2001331048-1051
13
1400
1200
1000
800
Cyclosporine (ng/mL)
600
400
200
0
0
2
4
6
8
10
12
Hours Post Dose
14
Pharmacokinetic Variability of Neoral is
Greatest During the Absorption Phase
From Levy G. BioDrugs. 200115279-290.
15
Effect of Predictor Variables on Primary Outcome
As Analyzed by the Cox Regression Model
Variable Coefficient SE (coef)
z P Dose (mg/kg) ?0.046409
0.033154 ?1.400 .1616 C0 (ng/mL)
0.000212 0.000503 0.422 .6731
SE (coef) Standard error (coefficient). z
Coefficient / SE (coef). C0 Trough CsA
concentration.
Levy G. et al., Transplantation, 2002, 73, 953-59.
16
Cyclosporine Exposure (AUC0-4) Related to Risk of
Graft Rejection and Toxicity
Living-Donor HLA identical recipients (n13)
were not included in the analysis of acute
rejection data
Mahalati K. et al., Transplantation, 1999, 68,
5562.
17
Effect of Predictor Variables on Primary Outcome
As Analyzed by the Cox Regression Model
Variable Coefficient SE (coef)
z P Dose (mg/kg) ?0.046409
0.033154 ?1.400 .1616 C0 (ng/mL)
0.000212 0.000503 0.422 .6731 C2
(µg/mL) ?0.000985 ?0.000247 ?3.985 .0001
SE (coef) Standard error (coefficient). z
Coefficient / SE (coef). C0 Trough CsA
concentration. C2 CsA concentration at 2 hours
post-dose.
Levy G. et al., Transplantation, 2002, 73, 953-59.
18
AUC04 Target Reached by Day 5 Associated with
Significantly Lower Incidence of Acute Rejection
HLA-identical LD recipients excluded Mahalati
K. et al., J Am Soc Nephrol 2001,12,828-33.
19
C2 Monitoring Resulted in Similar Safety Profile
C0 n 158
C2 n 148
Serious Adverse Events 42 42 AE Drug
related 8 9 Serious infections 17
23 Acute Renal Failure 20.8 25.9 CNS
disorders 10.7 9.5 Hypertension 42 48

Levy GA et al. Transplantation. 200069S387.
20
Mycophenolic Acid
21
MPA Time-Concentration Comparison
720 mg EC-MPA
1000 mg MMF
10
Plasma MPA concentration (?g/mL)
1
0.1
0
2
6
8
10
4
Time (hour)
22
IMPDH Inhibition post oral MPA dose
Budde et al, Transplant Proc, 34, 17481750 (2002)
23
Renal Txp Rejection and MPA AUC
Bullingham et al, Transplant Proc, 28, 925 (1996)
24
MPA Concentration Controlled Trial
48
50
50
Low (0.9 g/d)
MMF Dose
Intermediate (2.3 g/d)
40
40
High (4.1 g/d)
31
30
30
Acute rejection ()
Withdrawal ()
23
20
20
13
12
11
10
10
61 90
16 30
32 60
61 90
16 30
32 60
0
0
Target AUC (µgh/mL)
Target AUC (µgh/mL)
Van Gelder T, et al. Transplantation 1999 68(2)
261-266
25
mTOR / Proliferation Inhibitors
Sirolimus (rapamycin)
Everolimus (RAD001)
Synthetic derivative
Macrocyclic lactone produced by Streptomyces
hygroscopicus
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mTOR Inhibitor Mechanism of Action

• Rapa/RAD FKBP12 ---gt inhibition of a
  multifunctional serine-threonine kinase,
  mammalian target of rapamycin (mTOR)
• control a wide range of growth related cellular
  activities including transcription, translation,
  and reorganization of actin cytoskeleton
• inhibits both co-stimulatory activation and
  cytokine-driven pathways
• inhibitory action on cell growth and proliferation

27
Blood Everolimus Time - Concentration
28
Everolimus Freedom from rejection

• Lower therapeutic concentration 3 ng/ml

100
90
80
70
60
50
Patients free of rejection ()
40
Cmin gt 7 ng/ml (RR 0.85)
30
Cmin 3-7 ng/ml (RR 1.0)
20
Cmin lt 3 ng/ml (RR 2.8)
10
0
1
2
3
4
5
6
Months
29
Everolimus and Hyperlipidemias
10
0.75 mg BID
9

• Cholesterol
• Triglycerides

8
1.5 mg BID
7
6
5
Concentration (mmol/L)
4
3
2
1
0
0
1
2
3
4
5
6
Month
30
Everolimus Therapeutic range
100

• freedom from rejection
• hypertriglyceridemia
• thrombocytopenia

90
80
70
60
50
Patients with response ()
40
30
20
10
0
1
10
100
Everolimus Cmin (ng/ml)
31
Exposure-Creatinine Clearance Response Surface
The RAD and cyclosporine axis numbers correspond
to the concentration quartiles in ascending
order from 1 to 4. This view is with low exposure
to
both drugs at the front (groups 1 and 1).
32
FTY720
Synthetic structural analog of myriocin, a
metabolite of the ascomycete Isaria sinclairii
33
FTY720-P Signals EDG-6 and EDG-8 Receptors on
Lymphocytes
FTY720
EDG-6,-8 (EC50 gt1,000 nM)
FTY720-P
P
Homing Chemokines (SLC, ELC)
EDG-6 (EC50 43 nM)
CCR7
P
EDG-8 (EC50 37 nM)
MIGRATION
34
Allogeneic Mixed Lymphocyte Reaction (rat)
FTY720 Cyclosporine Tacrolimus
? ? ?
IL-2 Activity (U/mL)
0.001
0.01
0.1
1
10
100
1000
Concentration (nM)
35
FTY720 Time Concentration
36
Mean (SD) FTY720 Blood Concentration vs Time
FTY720 (ng/mL)
2.5 mg
1 mg
0.5 mg
0.25 mg
Week 12
37
FTY720 Effect on Lymphocyte Count
Placebo
FTY 1.25
FTY 5.0
38
FTY720 First Biopsy Confirmed Acute Rejection
Rate (weeks 0-12)
40
34.9
30
23.3
17.5
20
17.1
9.8
10
0
0.25mg
0.5mg
1.0mg
2.5mg
MMF 2.0g
FTY720
39
Study 121 Efficacy Endpoints (Months 0-12)
p 0.073
p 0.054
p0.064
40
Conclusions

• Renal transplantation requires the use of
  multiple drug regimens
• A primary effect response relationship has been
  established for drugs used in transplantation
• This relationship has been helpful in
  establishing safe and efficacious drug dosing
  regimens
• Secondary effect response relationships (drug
  combinations) are still being explored
• Continued exploration of effect - response
  relationship is resulting in further refinement
  of clinical use of these drugs
• There is increasing interest in clearly
  establishing effect - response relationship early
  in transplant drug development