Thymoglobulin ® Dosing

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 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-