Thymoglobulin ® Dosing

Report
Joong Kyung Kim, MD.
Division of Nephrology, Internal Medicine
Bong Seng Memorial Hospital, Busan, Korea
2013.1.3. Thailand
Three Major causes of ESRD
Fig.1. Three major causes of end stage renal disease patients who were initiated renal
replacement therapy in each year. (DM: diabetic nephropathy, CGN: chronic
glomerulonephritis, HTN: hypertensive nephrosclerosis).
Note increase of DM and decrease of CGN.
Prevalence of Renal Replacement Therapy
Patient Number of RRT
Fig. 2. Patient numbers of renal replacement therapy at the end of each year.
RRT modalities
Fig. 4. Proportion of renal replacement modalities, annual prevalence and incidence.
HD: hemodialysis, PD: peritoneal dialysis, KT: kidney transplantation.
Kidney transplantation
Fig.5. Annual number of kidney transplantation in Korea (including data from KONOS:
Korean Network for Organ Sharing).
* Survived KT waiting patient number at the end of each year.
1. Pharmacology of Thymoglobulin
2. Clinical Indication of Thymoglobulin
- Induction
- Rescue Therapy
- as a Bridge Therapy in delays of CNI
administration
Thymoglobulin® Production
Thymoglobulin® is a purified, pasteurized, gamma immune globulin
obtained by immunization of rabbits with human thymocytes
Thymus Immunogen
Production
Rabbit Sera
Production
Purification and Viral
Reduction of IgG
Fill/Finish
Data on file. Genzyme Corporation
Cellular Targets
The polyclonal antibody contains cytotoxic antibodies directed against a broad
array of antigens
T lymphocytes
CD3/TCR,
CD2, CD4, CD5,
CD6, CD7, CD8,
CD25,CD28, CD30,
CD45, CD80, CD86,
CTLA-4, VLA-4,
LFA-1, LPAM-1,
CCR5, CCR7, CXCR4,
HLA I, β2-M
NK cells
CD2, CD45,
CD56
B Lymphocytes
CD19, CD20, CD25,
CD27, CD30, CD32,
CD38, CD40, CD45,
CD86, CD95, HLA-DR
Plasma cells
CD138
Granulocytes
Monocytes
CD4, LFA-1,
CD45, CD86, VLA-4,
CD126, LPAM-1, HLA I
Endothelium
ICAM-1, ICAM-2, ICAM-3
The mechanism of action of Thymoglobulin is derived from nonclinical (in vitro or animal) data.
The clinical relevance of these data is unknown.
Bourdage JS, et al. Transplantation. 1995;59:1194
Rebellato LM, et al. Transplantation. 1994;57:685
Bonnefoy-Berard N, et al. Transplantation. 1991;51:669
Pharmacodynamics of Thymoglobulin®
 The polyclonal nature of Thymoglobulin®
: multiple effects on the immune system1
 Thymoglobulin triggering
- dose-dependent central and peripheral T cell depletion
- complement-dependent lysis and/or T cell activation
- apoptosis
 Preclinical investigation demonstrates that Thymoglobulin has functional
effects
on lymphocytes including modulation of key cell surface molecules4
 Following lymphocyte depletion, altered homeostasis can be observed with a resulta
nt decreased ratio of CD4+/CD8+ T cells5 and an increase in CD4+CD25+Foxp3+ T reg
ulatory cells (as shown in ex vivo and in vitro studies)6,7
1Mohty
M. Leukemia. 2007; 1-7.
X, et al. Transplantation. 2001;71:460-468.
3Starlz et al. Lancet 2003; 361:1502-1510
4Michallet M-C, et al. Transplantation. 2003;75:657.
5Mueller TF. Transplantation 1997;64:1421-1437.
6Lopez et al. J Am Soc Nephrol. 2006;17:2844–2853
7Lopez et al. Am J Transplant. 2008;8(s2):404.
2Préville
Pharmacodynamics of Thymoglobulin®
cont.
 Additional hematologic effects, including depletion of white
blood cells (WBC) and platelets
 Note that anti-red blood cell antibodies are removed as
a result of the hemoadsorption step in the manufacturing
process of Thymoglobulin
 Cytokine release may also occur after Thymoglobulin therapy
1Gaber
et al. Transplantation 1998;66:29-37.
et al. Transplantation 1999;67:1011-1018.
3Brennan et al. New Engl J Med 2006;355:1967-1977.
4Guttnann et al. Transpl Proc 1997;29:24.
2Brennan
Half-life of Thymoglobulin®
Reported Half-life
Thymoglobulin® dosing
Population
Reference
2.04-7.92 days (active)
From 3 doses x 2.5 mg/kg (7.5 mg/kg)
to 4 doses x 10 mg/kg (40 mg/kg) prior
to HSCT
Pediatric
Seidel,
2005
median of 15 days (total)
1 mg/kg on day -4, then 3mg/kg on
days -3, -2, -1 prior to HSCT
Pediatric
Call, 2009
2.5 mg/kg then 1.5mg/kg/day for 5 to 7
44.2 hours (total - initial T1/2)
days after renal or cardiac transplant or
13.8 days (total - terminal
1.25 mg/kg/day for 10 days after renal
T1/2)
transplant
Adult
Guttmann,
1997
10 days (total - initial T1/2)
30 days (total - terminal T1/2)
1.5mg/kg for 7-14 days for treatment of
renal allograft rejection
Adult
Regan,
2001
14days (total - initial T1/2)
30 days (total - terminal T1/2)
7 days (active-initial T1/2)
29 days (active-terminal T1/2)
2.5 mg/kg for 4 days (total of 10mg/kg;
n=3)
1.5 mg/kg for 4 days (total of 6 mg/kg;
n=22).
Adult
Waller,
2003
Factors Potentially Affecting Clearance:
Plasma exchange
 Thymoglobulin’s depletional effects can be seen soon after treatment, so
some level of T cell depletion is likely achieved
 in crossmatch-positive or ABO-incompatible adult kidney transplants
have concomitantly administered thymoglobulin and plasma exchange
 Although some available Thymoglobulin would have been removed from
the plasma
1 Gloor
J, et al. Am J Transplant 2003;3:1017-1023.
Gloor J, et al. Transplantation 2004;78:221-7.
3Gloor J, et al. Transplantation 2005;80:1572-7.
4 Stegall M, et al. Am J Transplant 2006;6:346-51.
5 Thielke J, et al. Transplant Proc 2005;37:643-4.
6 Thielke J, et al. Transplantation 2009;87:268-73.
7Akalin E, et al. Clin J Am Soc Nephrol 2008;3:1160-7.
2
Factors Potentially Affecting Clearance:
Day -1
Day 0
PP
PP
PP
Day 1
Day 3
Day 5
Day 7
1.5mg/kg
ATG
1.5mg/kg
ATG
1.5mg/kg
ATG
1.5mg/kg
ATG
PP
ATG
Day -3
PP
ATG
Day -5
PP
ATG
PP
ATG
PP
ATG
PP
ATG
Plasma exchange
Day 9
Day 30
Transplant
2mg/kg
ATG
2mg/kg
ATG
 Blood samples were collected 5 minutes before and 30 minutes after each
plasmapheresis session on Days 1,5 and 9
 Another blood sample was collected 30 minutes after the end of the ATG
infusion on Days 1, 5, 9
 A final blood sample was collected on post-operative day 30
Ipema H, et al. ATC 2010. Abstract 612.
Factors Potentially Affecting Clearance:
Plasma exchange
Average ATG concentrations (ug/mL, n=5)
Pre-PP
Day
Total
Active
Plasma exchange
Total
Active
Post-PP
Total
Active
Post-ATG
Total
Active
1
14.88
2.4
6.4
0.7
5.83
0.49
22.2
3.78
5
19.05
2.52
8.27
1.39
7.45
0.78
30.01
5.51
9
18.03
2.68
6.68
2.18
5.75
1.19
24.96
8.08
 Total ATG levels decreased an average of 59.8 ± 13.9% after each PP session, and active
ATG levels decreased by an average of 56.8 ± 17.1%.
Ipema H, et al. ATC 2010. Abstract 612.
Factors Potentially Affecting Clearance
Intravenous Immunoglobulin (IVIG)
 The co-administration of IVIG and Thymoglobulin® have not
reported any apparent drug-drug interactions
Dialysis
 Gamma globulin proteins are typically not removed by
dialysis; however, it is theoretically possible that some
nonspecific protein binding to a dialysis membrane could
occur
 It is recommended that the full dose of Thymoglobulin be
administered after dialysis treatment
1Glotz,
et al. AJT 2002;2:758-60.
et al. AJT 2003;3:1017-23.
3Akalin, et al. Transplantation 2003;76:1444-7.
4Gallay et al. Clin Transplant 2004;18:327-31.
2Gloor,
Mechanisms of T Cell Depletion by Thymoglobulin
Apoptosis via ActivationInduced Cell Death (AICD)1-4
FasL
Fas
Target Cell
Activated
NK Cell
Antibody-Dependent
Cell Cytotoxicity (ADCC)3,5
Target Cell
Killing
C1q
Effector Cell
Complement-Dependent
Cytotoxicity (CDC)1,4,5
Complement
Activation
Lysis
Target Cell
Membrane Attack
Complex
Direct Killing by Effector Cell
Juliusson G, et al. Bone Marrow Transplant. 2006;37(5):503-510.
T Lymphocyte Depletion by Thymoglobulin
 Profound lymphopenia (>50% depletion) can be seen as early as
24 hours after infusion and can persist up to one year after
treatment period
 Peripheral lymphocyte depletion is dose-dependent4
 In addition to peripheral lymphocyte depletion, central
depletion(lymphoid tissue of the spleen and lymph nodes)3,4
 Thymoglobulin® has been shown to target a broad range of
different lymphocyte subsets1,5
1Gaber
A, et al. Transplantation 1998; 66:29-37.
D, et al. Transplantation 1999; 66: 29-37.
3Starlz et al. Lancet 2003; 361:1502-1510
4Preville X, et al. Transplantation 2001; 71:460-468.
5Guttmann R, et al. Transpl Proc 1997; 29:24.
2Brennan
T-Lymphocyte Depletion by Thymoglobulin®
The phase 3 study by Gaber et al (1998) reported
more profound and more prolonged lymphocyte
depletion with Thymoglobulin® compared with ATGAM
Similarly, a comparative trial by Brennan et al (1999)
reported more profound and prolonged lymphocyte
depletion with Thymoglobulin compared with ATGAM
500
T Cells/mm3
400
P=0.004 (CD2)
P=0.004 (CD3)
300
200
Atgam
CD3
CD2
100
Thymoglobulin®
0
001
2
3
4
5
6
7
8
9
10
11
Days After Treatment
12
13
14
CD3
CD2
Absolute Lymphocyte Count (x1000)
3.0
2.5
P<0.007
2.0
P<0.007
1.5
Atgam
1.0
Thymoglobulin®
0.5
360
0.0
0
30
60
90
120
150
180
210
240
270
300
330
Days After Treatment
Thymoglobulin® Dosing: 1.5 mg/kg for 7-14 days for treatment (Gaber) or prevention (Brennan) of renal
allograft rejection
Gaber et al, Transplantation 1998;66(1):29-37
Brennan et al, Transplantation 1999;67(7):1011-1018
80
60
Atgam
40
CD4 Cells (%)
Thymoglobulin® Dosing: 2mg/kg for 5 days for
prevention of renal allograft rejection in
pediatric patients
MALG
20
Similar to previous reports, a study in pediatric
renal transplant patients by Brophy et al (2001)
reported more profound and more prolonged
lymphocyte depletion with Thymoglobulin®
compared with Atgam and Minnesota ALG
(MALG).
100
T Lymphocyte Depletion by Thymoglobulin®
Thymo
1
2
3
4
5
6
7
8
9
10
1
2
3
4
5
6
7
8
Days After Treatment
9
10
80
60
40
CD3 Cells (%)
Thymo
MALG
MALG
Atgam
20
80
60
40
Atgam
20
CD8 Cells (%)
100
100
Days After Treatment
Thymo
1
2
3
4
5
6
7
8
9
10
Days After Treatment
Brophy et al, Pediatr Transplant 2001; 5:174-178
Lymphocyte Depletion by Thymoglobulin
Peripheral Depletion
Central Depletion
Percent of Lymphocyte Subsets
Guttmann et al 1997 reported profound decreases (absolute and
relative) in a broad range of lymphocyte subsets in peripheral
blood throughout the 3 months after Thymoglobulin® treatment
CD45
100
CD2
80
CD3
CD8
60
40
Thymoglobulin® Treatment:
A single dose of 5mg/kg of
Thymoglobulin was administered
to solid organ transplant recipients
several hours prior to transplant.
CD4
CD25
20
CD16
0
PRE
Starzl et al 2003 reported “striking”
lymphocyte depletion following
Thymoglobulin treatment in lymph
nodes biopsied at the time of surgery
WI
W3
W5
W7
W9
W11
Weeks After Treatment
Thymoglobulin® Dosing: 1.25mg/kg for 10 days after renal
transplant (French Center); 2.5mg/kg dose then 1.5mg/ kg/day
for 5-7 days after renal or cardiac transplant (Canadian Center)
Guttmann et al, Transplant Proc 29:24S-26S, 1997
Starzl et al, Lancet 361:1502-1510, 2003
Hematologic Effects of Thymoglobulin
Consistent with previous reports,
Brennan et al (2006) reported initial
decreases in white blood cell (WBC)
and platelet counts following
Thymoglobulin® therapy. In this study,
counts returned to normal by day 14.
Mean WBC Count (x10-3/mm3)
26
24
22
20
18
Mean Platelet Count (x10-3/mm3)
240
Thymoglobulin®
220
Basiliximab
200
180
160
140
120
100
0
16
0
15
30
45
60 75
90 105 120 135 150 165 180 195 210 225 240 255 270 285 300 315 330 345 360
14
Days After Treatment
12
10
Basiliximab
8
6
Thymoglobulin®
4
Thymoglobulin® Dosing: 1.5
mg/kg for 5 days for prevention of
renal allograft rejection
2
0
0
15
30 45
60 75 90 105 120 135 150 165 180 195 210 225 240 255 270 285 300 315 330 345 360
Days After Treatment
Brennan et al. N Engl J Med 355(19):1967-1977. 2006
Leukopenia and Thrombocytopenia:
dosage adjustment
WBC count
(cells/mm3)
platelet count
(cells/mm3)
Thymoglobulin
Dose
> 3,000
> 75,000
Full dose
2,000 to 3,000
50,000 to 75,000
Reduce dose by half
< 2,000
< 50,000
Consider stopping treatment
*Dose adjustments due to leukopenia and/or thrombocytopenia are not recommended when
Thymoglobulin is used for hematologic indications
Thymoglobulin: Core Safety Information; Rev. 11/06
 Transient increases in the cytokines TNF and IL-6
in the peripheral blood in the first 24 hours after
Thymoglobulin® infusion
 Peak levels of TNF and IL-6 were reported at
approximately 3 hours after starting the infusion
 Elevations in other cytokines, such as IL-1 and
IFNγ were not observed in this study
Thymoglobulin® Dosing: 1.25mg/kg for 10 days
after renal transplant (French Center); 2.5mg/kg
dose then 1.5mg/ kg/day for 5-7 days after renal
or cardiac transplant (Canadian Center)
mean
1600
+95% CI
-95% CI
1200
800
400
0
4000 0
IL-6 (pg/ml)
Guttmann et al (1997) reported
TNF (pg/ml)
Cytokine Release after Thymoglobulin®
6
12
18
24
30
36
42
48
Peripheral blood cytokines
(TNF and IL-6) are elevated
during the first 24 hours
after Thymoglobulin®
3000
2000
1000
0
0
6
12
18 24 30 36
Time (hours)
42
48
Guttmann et al, Transplant Proc 29:24S-26S
Thymoglobulin induction Protocol
POD
Thymoglobulin
Steroids
MMF
peri-op
1.5 mg/kg IV
M-PDS 500 mg IV
1 gm IV/PO pre-op
infuse peripherally
given 1 hour prior to
then
over 12 hours
Thymoglobulin
1 g PO/IV Q12h
1.5 mg/kg IV
M-PDS 250 mg IV
infuse peripherally
given 1 hour prior to
over 6 hours
Thymoglobulin
of transplant
1.5 mg/kg IV
M-PDS 125 mg IV
Adjust to
infuse peripherally
given 1 hour prior to
over 6 hours
Thymoglobulin
within 6
hours of
transplant
1
2-4
Tacrolimus
1-3mg PO q 12h
1 g PO Q12h
.
within 48hours
trough levels of
10-15 ng/ml
Prednisone
5
20 mg PO-daily
.
.
Thymoglobulin induction protocol
in Bong-Seng Memorial Hospital
Thymoglobulin (1~1.5mg/kg)
Start within 6 hours
FK 0.1mg/day
before transplant
Trough level 10~12 ng/ml
MMF 1,5g/day
1.5/day
Steroid
500mg
before
250mg
thymo
125mg
(Day)
-1
Tx.
1
2
8~10 ng/ml
20mg/day
3
4
5
1M
■ The following additives should be placed in 500ml 0.9% or 0.45% Nacl and the IV bag given by peripheral administration
1. Thymoglobulin 1.5mg/kg/day (max 150mg/day). 2. Heparin 1,000 units 3. Infuse peripherally over 12hrs at 1 st time
■ Premedicate with steroid dose, antihistamines and acetaminophen PO/IV 1hour prior to Thymoglobulin use
CASE 1
 F / 61 yr
 1993 – ESRD d/t prob. CGN
 1993 – CAPD OP.
 1995 – 1st KTP with LUR (3/6 mismatch)
 1998 – Acute cellular rejection (GK Bx.)

PDS pulse & CsA/MMF -> FK/AZA
 1999 – Hemodialysis via Lt. AVF shunt
 2008 – 2nd KTP with deceased donor (4/6 mismatch)

PRA class I 67.9%, class II 91.7%, No present DSA
Induction Therapy in High Risk Kidney
Transplantation
1.
2.
3.
4.
5.
2nd KT
High PRA(PRA class I 67.9%, class II 91.7%, )
History of intractable rejection in 1st KT
Deceaced Donor
Old age(to avoid CNI toxicity)
Clinical course of CASE 1
5
Serum Cr (mg/dL)
4
4.1
3
2
2.1
1.4
1
0
1.1
U/O (cc)
0
1.1
7700
3460
3990
4020
4720
1
2
3
4
5
1
0.9
0.9
0.9
4225
3420
2900
2800
6
7
14
21
Post OP (day)
Thymoglobulin (1.5mg/kg)
FK
trough level
(ng/dL)
7.6
8.2
7.5
7.0
9.1
MMF 1.5g/day
PDS
500mg
250mg
125mg
60mg
30mg/day
6.9
7.4
Thymoglobulin vs. ATGAM for Induction Therapy
Acute Rejection through 10 Years
100
80
Thymo
Percent
Atgam
60
42%
Acute Rejection
40
P=0.004
20
+
+ +++ +
+
+
+++
+
+
+
11%
Acute Rejection
+ ++ +
0
0
2
4
6
8
10
Time after Transplant (years)
Hardinger et al. Transplantation. 86(7):947-952, 2008
PLEASE SEE FULL THYMOGLOBULIN® (ANTI-THYMOCYTE GLOBULIN [RABBIT]) PRESCRIBING INFORMATION INCLUDING BOXED WARNING
Thymoglobulin vs. ATGAM for Induction Therapy
Event-Free Survival through 10 years
*Freedom from acute rejection, graft loss, and death
100
Percent Survival
80
60
48%
P=0.011
40
Thymo
Atgam
20
29%
0
0
2
4
6
8
10
Time after Transplant (years)
Hardinger et al. Transplantation. 86(7):947-952, 2008
Thymoglobulin vs. Basiliximab for induction therapy:
Efficacy Endpoints at 12 Months
60%
P=0.34
Thymoglobulin®
Basiliximab
50%
P=0.54
P=0.02
40%
P=0.02
30%
20%
P=0.68
10%
P=0.90
0%
Quad
Triple*
BPAR Graft Loss Death
DGF
The use of Thymoglobulin was associated with a 39% relative reduction in BPAR
Quad = quadruple endpoint, BPAR, graft loss, death, DGF
*Triple = Triple endpoint, BPAR, graft loss, death, calculated in an ad hoc analysis
Brennan et al. N Eng J Med 355:1967-77, 2006
Thymoglobulin vs. Basiliximab for induction therapy:
Severity of Acute Rejection
30%
P=0.02
Thymoglobulin®
25%
Basiliximab
25.5%
20%
15%
15.6%
P=0.005
10%
8.0%
5%
1.4%
0%
BPAR
Antibody Treated AR
Brennan et al. N Eng J Med 355:1967-77, 2006
Trends in the use of induction antibodies
in the US from 1997 to 2006.
Padiyar A. et al. Am J Kidney Dis 54:935-944, 2009
Trends in the Thymoglobulin Use in US
:Report of the TAILOR™ registry
THYMOGLOBULIN DOSING
MEAN CUMULATIVE DOSE
± SD
MEDIAN CUMULATIVE
DOSE [range]
mg/kg
5.29 ± 1.88
5.00 [1.56-15.00]
THYMOGLOBULIN ADMINISTRATION
PRE-PERFUSION*
2468 (87.8%)
CENTRAL LINE
2071 (89.2%)
DOSING INTERUPTIONS
PATIENTS REQUIRING DOSE
INTERUPTION
821 (35.5%)
INTERUPTIONS DUE TO
LEUKOPENIA
258 (11.1%)
INTERUPTIONS DUE TO
THROMBOCYTOPENIA
75 (3.2%)
50%
45%
40%
35%
30%
25%
20%
15%
10%
5%
0%
46.6%
35.4%
18.0%
N=1081
N=823
N=418
1.5-<5mg/kg
5-<7mg/kg
7-15mg/kg
Cumulative Thymoglobulin Dose
Gaber et al. Transplantation 94:4, 2012
CASE 2
 M / 62 yr
 1991 – Colon cancer
 2010 – Both ureteral stone remove
 2010 – ESRD d/t prob. obstructive nephropathy
 2010 – Hemodialysis via AVF shunt
 2011 – KTP with LUR (5/6 mismatch)

PRA class I 0 %, class II 0 %
 2011 – 1st GK Biopsy (Acute cellular rejection)
 2012 – 2nd GK biopsy (Acute cellular rejection)
Clinical course of CASE 2
3
Serum Cr (mg/dL)
1st GK Bx.
Steroid
pulse
2nd
GK Bx.
Thymoglobulin
(1.5mg/kg for 5
days)
2
1
0
1
3
6
9
12
15
Post OP (Month)
FK
MMF
PDS
18
21
24
CASE 3
 F / 58 yr
 1999 – DM, HTN
 2008 – ESRD d/t diabetic nephropathy
 2008 – CAPD start
 2009 – KTP with younger brother (3/6 mismatch)




5 times episode of cross match positive
PRA class I 78.6 %, class II 75.0 %
Pre KTP plasma exchange (3 times) was done d/t high PRA
Cyst of GK aspiration (30cc) & absorbable gelatin sponge add
 POD 4 – GK biopsy (Acute antibody mediated rejection)
Clinical
course
of
CASE
3
5
4.5
Serum Cr (mg/dL)
4
3.4
GK Bx.
3
Rituximab
(375mg/mm2 )
2.2
2
1.8
1.6
1.7
1.3
1
1.3
1.2
1.4
1.2
1.4
Plasma exchange (1.0 plasma volume)
0
-5
-3
0
2
4
6
8
10
12
14
21
28
8.6
7.8
Post OP (day)
Plasma exchange
(1.0 plasma volume)
Thymoglobulin (1.0mg/kg)
7.3
FK trough level (ng/dL)
4.0
500mg
250mg
4.2
4.9
4.8
4.8
2.0g/day
MMF 1.5g/day
PDS
4.6
125mg
60mg
30mg/day
Thymoglobulin as a treatment of acute rejection
- To avoid CNI toxicity
- To spare CNI
- To delay of CNI administration
- To early withdraw steroid
Thymoglobulin induction protocol
for CNI sparing in Bong-Seng Memorial Hospital
Thymoglobulin
(1.0 mg/kg)
FK 0.1mg/day Trough level 8~12 ng/ml
MMF 1.5g/day
Steroid
500mg
before
thymo
(Day)
-1
500mg
Tx.
1
250mg
2
120mg
3
8 ng/ml
1.0/day
60mg
4
30mg/day
5
1M
■ The following additives should be placed in 500ml 0.9% or 0.45% Nacl and the IV bag given by peripheral administration
1. Thymoglobulin 1~1.5mg/kg/day (max 150mg/day). 2. Heparin 1,000 units
■ Premedicate with steroid dose, antihistamines and acetaminophen PO/IV 1hour prior to Thymoglobulin use
Thymoglobulin give chance to spare CNI use
 Single shot ATG induction can allow postoperative CNI holiday in
patients with heart transplantation
- renal sparing and safe strategy 1
 A CD3+ count-based thymoglobulin induction regimen permits
delayed introduction of CNI in KTP 2
 Thymoglobulin can preserve renal function in patients with liver
transplantation and delayed initiation of CNI3
1Thorac
cardiovasc Surg 2009; 56 - V177
et al. Clin Transplant 2012: 26: 900–909
3Bajjoka et al. Liver Transplant 14:66-72, 2008
2Wang
Conclusion. TMG seems to be a safe alternative induction strategy in
patients for SF immunosuppression in pediatric renal transplantation.
Extended follow-up and greater enrollment are necessary to fully explore
the impact of TMG dosing on viral replication posttransplantation
Long-term Infectious Complications by
Thymoglobulin Dose :Report of the TAILOR™ registry
Cumulative Thymoglobulin Dose
1.5 to <5mg/kg
5 to <7mg/kg
7 to 15mg/kg
Total
n=862
n=664
n=290
N=1816
25 (2.9%)
38 (5.7%)
14 (4.8%)
77 (4.2%)
0
1 (0.2%)
0
1 (0.1%)
EBV Infections
6 (0.7%)
2 (0.3%)
0
8 (0.4%)
Fungal Infections
17 (2.0%)
16 (2.4%)
10 (3.4%)
43 (2.4%)
179 (20.8%)
189 (28.5%)
83 (28.6%)
451 (24.8%)
12 Months Post-transplant -TAILOR
CMV Infections
- Invasive CMV disease
Bacterial Infections
N=2322
12 Months Post-transplant -UNOS
K-M Freedom from Infection-related Death
-
-
-
N=1174
5 Years Post-transplant -UNOS
K-M Freedom from Infection-related Death
99.9%
-
-
-
99.1%
Gaber et al. Transplantation 94:4, 2012
Viral Infections and Antiviral Prophylaxis
:Report of the TAILOR™ registry
Higher Incidence of Viral Infections at 6 months
Among Patients Not Receiving Prophylaxis
Percent Receiving Antiviral Prophylaxis
10%
None
90%
Received
Prophylaxis
Incidence of Viral Infections
14%
12%
10%
9.60%
P=0.047
8%
5.60%
6%
4%
2%
103 / 1846
14 / 146
0%
Received
Prophylaxis
No Prophylaxis
 The majority of recipients received antiviral prophylaxis
 Viral infections were more common among patients not receiving prophylaxis
Gaber et al. Transplantation 94:4, 2012
PTLD by Thymoglobulin dose
:Report of the TAILOR™ registry
Cumulative Thymoglobulin Dose
1.5 to <5mg/kg 5 to <7mg/kg
7 to 15mg/kg
Total
12 Months Post-transplant
-per UNOS
n=1081
n=823
n=418
N=2322
PTLD incidence
6 (0.6%)
3 (0.4%)
1 (0.2%)
10 (0.4%)
-
-
-
99.7%
K-M Freedom from PTLD
5 Year Post-transplant
-per UNOS
K-M Freedom from PTLD
•
•
•
N=1174
-
-
-
99.1%
PTLD incidence did not correlate with Thymoglobulin dose
PTLD was more common in EBV D+R- (known risk factor), than other combinations
Of 58 EBV D+R- transplants in TAILOR, the majority (95%) did not develop PTLD
Gaber et al. Transplantation 94:4, 2012
Summary
1.
The pharmacodynamics of Thymoglobulin® are complex due
to its polyclonal nature
2. Thymoglobulin® acts primarily by triggering dose-dependent
central and peripheral T cell depletion
3. Thymoglobulin can be used in induction therapy in high risk
renal transplantation
4. Thymoglobulin is alternative good choice in rescuing allograft
rejection
5. With the aid of a Thymoglobulin, CNI sparing and early
withdrawal of steroid regimen can be tried
Conclusion
 Thymoglobulin is an effective and generally
well tolerated option for the prevention and
treatment of acute renal graft rejection in
renal transplantation
Thank you for your attention!
Dosage adjustment of Ganciclovir
Ccr
Induction
(mg/kg)
Interval
Maintenance
(mg/kg)
Interval
>70
5.0
12
5.0
24
50-69
2.5
12
2.5
24
25-49
2.5
24
1.25
24
10-24
1.25
24
0.625
24
<10
1.25
X 3/wk,
post HD
0.625
X 3 /Wk
Post HD
Total Duration: 1wk Induction +2wk Maintenance
1 Ample =250mg or 500mg
Use safely for 3 days(HD Pt give 70mg in one dose)

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