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Thymoglobulin (Anti-Thymocyte Globulin (Rabbit)) - Description and Clinical Pharmacology

 
 



DESCRIPTION

Thymoglobulin® [Anti-thymocyte Globulin (Rabbit)] is a purified, pasteurized, gamma immune globulin, obtained by immunization of rabbits with human thymocytes. This immunosuppressive product contains cytotoxic antibodies directed against antigens expressed on human T-lymphocytes.

Thymoglobulin is a sterile, freeze-dried product for intravenous administration after reconstitution with Sterile Water for Injection, USP (SWFI).

Each 10 mL vial contains 25 mg anti-thymocyte globulin (rabbit) as well as 50 mg glycine, 50 mg mannitol, and 10 mg sodium chloride.

After reconstitution with 5 mL SWFI, each vial of reconstituted product contains approximately 5 mg/mL of Thymoglobulin, of which >90% is rabbit gamma immune globulin (IgG). The reconstituted solution has a pH of 6.5 - 7.2. Human red blood cells are used in the manufacturing process to deplete cross-reactive antibodies to non-T-cell antigens. The manufacturing process is validated to remove or inactivate potential exogenous viruses. All human red blood cells are from US registered or FDA licensed blood banks. A viral inactivation step (pasteurization, i.e., heat treatment of active ingredient at 60°C/10 hr) is performed for each lot. Each Thymoglobulin lot is released following potency testing (lymphocytotoxicity and E-rosette inhibition assays), and cross-reactive antibody testing (hemagglutination, platelet agglutination, anti-human serum protein antibody, antiglomerular basement membrane antibody, and fibroblast toxicity assays on every fifth lot).

PHARMACOLOGY

Mechanism of Action

The mechanism of action by which polyclonal antilymphocyte preparations suppress immune responses is not fully understood. Possible mechanisms by which Thymoglobulin may induce immunosuppression in vivo include: T-cell clearance from the circulation and modulation of T-cell activation, homing, and cytotoxic activities. Thymoglobulin includes antibodies against T-cell markers such as CD2, CD3, CD4, CD8, CD11a, CD18, CD25, CD44, CD45, HLA-DR, HLA Class I heavy chains, and Ÿ2 micro-globulin. In vitro, Thymoglobulin (concentrations >0.1 mg/mL) mediates T-cell suppressive effects via inhibition of proliferative responses to several mitogens. In patients, T-cell depletion is usually observed within a day from initiating Thymoglobulin therapy. Thymoglobulin has not been shown to be effective for treating antibody (humoral) mediated rejections.

Pharmacokinetics and Immunogenicity

After an intravenous dose of 1.25 to 1.5 mg/kg/day (over 4 hours for 7-11 days) 4-8 hours post-infusion, Thymoglobulin levels were on average 21.5 mcg/mL (10-40 mcg/mL) with a half-life of 2-3 days after the first dose, and 87 mcg/mL (23-170 mcg/mL) after the last dose. During the Thymoglobulin [ Thymoglobulin is a registered trademark of Genzyme Corporation, Cambridge, MA 02142] Phase 3 randomized trial, of the 108 of 163 patients evaluated, anti-rabbit antibodies developed in 68% of the Thymoglobulin-treated patients, and anti-horse antibodies developed in 78% of the Atgam [ Atgam is a registered trademark of Pfizer Inc, New York, NY 10017] -treated patients (p=n.s.). No controlled studies have been conducted to study the effect of anti-rabbit antibodies on repeat use of Thymoglobulin. However, monitoring the lymphocyte count to ensure that T-cell depletion is achieved upon retreatment with Thymoglobulin is recommended. Based on data collected from a limited number of patients (Clinical study Phase 3, n=12), T-cell counts are presented in the chart below. These data were collected using flow cytometry (FACSCAN, Becton-Dickinson).

Clinical Trials

US Phase 3 Study

A controlled, double-blind, multicenter, randomized clinical trial comparing Thymoglobulin and Atgam was conducted at 28 US transplant centers in renal transplant patients (n=163) with biopsy-proven Banff Grade II (moderate), Grade III (severe), or steroid-resistant Grade I (mild) acute graft rejection. This clinical trial rejected the null hypothesis that Thymoglobulin was more than 20% less effective in reversing acute rejection than Atgam. The overall weighted estimate of the treatment difference (Thymoglobulin — Atgam success rate) was 11.1% with a lower 95% confidence bound of 0.07%. Therefore, Thymoglobulin was at least as effective as Atgam in reversing acute rejection episodes.

In the study, patients were randomized to receive 7 to 14 days of Thymoglobulin (1.5 mg/kg/day) or Atgam (15 mg/kg/day). For the entire study, the two treatment groups were comparable with respect to donor and recipient characteristics. During the trial, the FDA approved new maintenance immunosuppressive agents (tacrolimus and mycophenolate). Off-protocol use of these agents occurred during the second half of the study in some patients without affecting the overall conclusions (Thymoglobulin 22/43, Atgam 20/37; p=0.826). The results, however, are presented for the first and second halves of the study (Table 1). In Table 1, successful treatment is presented as those patients whose serum creatinine levels (14 days from the diagnosis of rejection) returned to baseline and whose graft was functioning on day 30 after the end of therapy.


Table 1: Response to Study Treatment by Rejection Severity and Study Half
  Sucess/n    Total    First Half   Second Half  
      Thymoglobulin          Atgam          Thymoglobulin         Atgam         Thymglobulin         Atgam    
 Risk Factor:            
 Baseline            
 Rejection Severity:            
    Mild  9/10 (90.0%)   5/8 (62.5%)  5/5 (100%) 1/3 (33.3%)   4/5 (80.0%) 4/5 (80%) 
    Moderate  44/58 (75.5%)  41/58 (70.7%)  22/26 (84.6%)  22/32 (68.8%)  22/32 (68.8%)  19/26 (73.1%)
    Severe  11/14 (71.6%)  8/14 (57.1%)  6/8 (75.0%)  3/8 (37.5%)  5/6 (83.3%)  5/6 (83.3%)
      Overall  64/82 (78.0%)  54/80 (67.5%)  33/39 (84.6%)  26/43 (60.5%)  31/43 (72.1%)  28/37 (75.7%)

Weighted estimate of difference
(Thymoglobulin – Atgam)

11.1% 1    19.3% -3.2%
Lower one-sided 95% confidence bound 0.07% 4.6% -19.7%
p Value 2    0.061 3    0.008 4    0.625

1 across rejection severity and study half
2 under null hypothesis of equivalence (Cochran-Mantel-Haenszel test)
3 one-sided stratified on rejection severity and study half
4 one-sided stratified on rejection severity


There were no significant differences between the two treatments with respect to (i) day 30 serum creatinine levels relative to baseline, (ii) improvement rate in post-treatment histology, (iii) one-year post-rejection Kaplan-Meier patient survival (Thymoglobulin 93%, n=82 and Atgam 96%, n=80), (iv) day 30 and (v) one-year post-rejection graft survival (Thymoglobulin 83%, n=82; Atgam 75%, n=80).


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