Rabbit Antithymocyte Globulin (Thymoglobulin®)
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- Deeks, E.D. & Keating, G.M. Drugs (2009) 69: 1483. doi:10.2165/00003495-200969110-00007
Rabbit antithymocyte globulin (rATG) [Thymoglobulin®; Thymoglobuline®] is a purified, pasteurized preparation of polyclonal gamma immunoglobulin raised in rabbits against human thymocytes that is indicated for the prevention and/or treatment of renal transplant rejection in several countries worldwide.
rATG induction in combination with immunosuppressive therapy is more effective in preventing episodes of acute renal graft rejection in adult renal transplant recipients than immunosuppressive therapy without induction. The efficacy of rATG induction is generally better than that of equine antithymocyte globulin (eATG) induction and generally no different from that of basiliximab or low-dose daclizumab induction in this patient population. However, in high-risk patients, rATG induction was more effective than daclizumab or basiliximab induction in preventing acute renal graft rejection. In the treatment of renal graft rejection in adult renal transplant recipients, rATG was more effective than eATG in terms of the successful response rate, although the agents generally did not differ with regard to most other endpoints.
Both induction and treatment with rATG are generally well tolerated, although adverse events, such as fever, leukopenia and thrombocytopenia, appear more common with rATG than with other antibody preparations. The overall incidence of infection associated with rATG induction was generally no different from that seen with eATG or basiliximab induction, although was higher with rATG than with basiliximab in high-risk patients. The incidence of cytomegalovirus (CMV) disease generally did not differ between rATG and eATG induction, and there was no significant difference between rATG and daclizumab induction with regard to the incidence of CMV infections or the proportion of patients who received treatment for a CMV episode or infection. Relative to basiliximab, the incidence of CMV infection was generally higher with rATG, except in high-risk patients. In the treatment of acute renal rejection, the nature and incidence of infections were generally similar with rATG and eATG. The incidence of malignancies is generally low with rATG therapy and generally does not differ from that seen with other agents.
Further prospective comparative studies would be beneficial in order to definitively position rATG with respect to other antibody preparations. In the meantime, available clinical data suggest that rATG is an effective and generally well tolerated option for the prevention and treatment of acute renal graft rejection in renal transplant recipients.
rATG displays specificity towards a wide variety of surface antigens on both immune system and endothelial cells. The precise mechanism(s) of action underlying its immunosuppressive efficacy is unclear, although T-cell depletion is considered to play a key role. Other mechanisms include lymphocyte surface antigen modulation, transcription factor activation, and interference with processes of immune system cells, such as cytokine production, chemotaxis, endocytosis, stimulation and proliferation. rATG may also induce apoptosis, antibody-dependent lysis or complement-mediated lysis of various immune system cells, and negate leukocyte-endothelial cell adhesion. Treatment with rATG sustained T-cell depletion more effectively than eATG in renal transplant recipients experiencing acute renal rejection. Moreover, rATG induction was at least as effective as eATG induction in depleting lymphocytes, and as expected, was associated with lower lymphocyte levels than basiliximab or daclizumab induction in renal transplant recipients.
Serum concentrations of rATG appear to increase during treatment with intravenous rATG, and the serum concentration of total rATG, but not active rATG, is closely related to the cumulative dose. Levels of rATG in serum decline steadily after infusion cessation, with an elimination half-life of 2–3 days after an initial dose of 1.25–1.5mg/kg, although the decline of active rATG levels appears to be more rapid. Among renal transplant patients who received rATG 1.5mg/kg/day for up to 14 days, rATG and active rATG were present at measurable levels in 81% and 12% of patients 90 days after initiation of therapy.
Prevention of Acute Renal Transplant Rejection: In two randomized, open-label, multicentre trials in adult renal transplant recipients, rATG induction in combination with tacrolimus-based immunosuppressive therapy was more effective than tacrolimus-based therapy without induction in preventing acute renal graft rejection at 6 or 12 months post-transplantation. In one of these studies, the incidence of biopsy-confirmed acute rejection (BCAR) in recipients of rATG induction with tacrolimus-based therapy did not significantly differ from that seen in recipients of rATG induction with ciclosporin-based therapy. Moreover, the median time to BCAR was >1 week longer with rATG induction therapy than with noninduction therapy, although there were no significant differences between regimens in terms of patient or graft survival.
rATG induction was generally more effective than eATG induction in adult renal transplant recipients receiving immunosuppressive therapy in a double-blind, single-centre trial. rATG recipients had a lower incidence of BCAR episodes and greater event-free survival than eATG recipients up to 10 years post-transplantation, and greater graft survival up to 5 years post-transplantation, although there was no significant between-group difference in terms of patient survival. Moreover, in three randomized, open-label, multicentre studies, the efficacy of rATG induction therapy was generally no different from that of basiliximab or low-dose daclizumab in adult renal transplant recipients receiving triple immunosuppressive therapy. There were generally no differences between rATG and these agents in terms of the incidence of BCAR, or patient or graft survival at 6 months or 1 year post-transplantation, with rATG and basiliximab also not differing with regard to the composite of BCAR, graft loss or death at these timepoints.
Induction with rATG was also effective in combination with corticosteroid-free immunosuppressive therapy in adult and paediatric renal transplant recipients in a prospective noncomparative study. Furthermore, rATG induction in combination with an early corticosteroid withdrawal immunosuppressive regimen provided efficacy not significantly different from that of an immunosuppressive regimen with standard corticosteroid use in adult renal transplant recipients in a randomized, multicentre trial.
rATG induction, in combination with triple immunosuppressive therapy, has also demonstrated efficacy in renal transplant recipients at high risk of acute rejection or delayed graft function. In a large, randomized, multicentre trial, the efficacy of rATG was generally no different to that of basiliximab at 1 year post-transplantation, with no significant between-group difference in the composite endpoint of first BCAR, delayed graft function, graft loss or death, or most of the individual components of the composite; however, the incidence of BCAR was lower with rATG than with basiliximab. In a similarly designed trial comparing rATG with daclizumab, rATG provided better efficacy in terms of the incidence of BCAR 1 year after transplantation and was associated with a longer median time to rejection, although the treatment groups did not significantly differ with regard to rates of patient or graft survival. Longer term, rATG may provide benefits over basiliximab up to 5 years post-transplantation, according to a retrospective analysis of one of these trials. Data from three retrospective studies indicated that rATG induction therapy is effective in African-American renal transplant recipients.
In two retrospective studies in paediatric renal transplant recipients, the efficacy of rATG in combination with immunosuppressive therapy in preventing episodes of acute rejection was not significantly different to that of immunosuppressive therapy alone or in combination with basiliximab at 1 year post-transplantation, whereas rATG was associated with fewer BCAR episodes than eATG up to 3 years post-transplantation in the largest of these studies. There were generally no differences between rATG and these regimens with regard to most other endpoints.
Treatment of Acute Renal Graft Rejection: In a large randomized, double-blind, multicentre, phase III trial conducted in adult renal transplant recipients receiving concomitant immunosuppressive therapy, more rATG than eATG recipients achieved the endpoint of successful response (i.e. a return of serum creatinine levels to baseline by end of treatment or within 14 days of treatment initiation), although the treatment groups generally did not differ in terms of graft survival at 30 days, graft function or the proportion of patients who had an improvement in rejection severity of one Banff grade. However, among those who achieved a successful response, fewer episodes of recurrent rejection occurred in rATG than eATG recipients within 90 days of treatment cessation, although there was no between-group difference in graft or patient survival 1 year after treatment completion.
Both induction and treatment with rATG were generally well tolerated in adult renal transplant recipients in clinical trials. More patients who received rATG induction in combination with immunosuppressive therapy experienced leukopenia, fever, serum sickness and thrombocytopenia than those who received immunosuppressive therapy without induction. In trials comparing rATG with other induction agents, rATG was associated with a lower median incidence of serious treatment-emergent adverse events than eATG, although it generally did not differ from basiliximab in terms of the incidence of any adverse events or serious adverse events, or from daclizumab in terms of the incidence or severity of adverse events. The most common selected adverse events (other than infection) reported in recipients of rATG and other induction agents were fever, gastrointestinal disorder, leukopenia and thrombocytopenia; rATG was associated with a higher incidence of leukopenia than basiliximab or eATG and a higher incidence of fever and thrombocytopenia than basiliximab in some studies. Adverse events considered to be study drug related occurred in more rATG than basiliximab induction recipients, with fever, gastrointestinal disorder, cutaneous rash and serum sickness being attributed to rATG. When used in the treatment of acute renal transplant rejection, the tolerability profile of rATG was generally similar to that of eATG, with fever, chills and leukopenia the most common adverse events reported in both treatment groups. However, compared with eATG, rATG was associated with a greater incidence of leukopenia and malaise, and a lower incidence of dizziness and dysuria.
rATG induction in combination with immunosuppressive therapy was generally less favourable than immunosuppressive therapy without induction with regard to the incidence of infection, particularly CMV. However, the overall incidence of infection associated with rATG induction was no different from that seen with eATG or basiliximab induction, although it was higher than with basiliximab in high-risk patients. In studies that assessed CMV parameters as primary tolerability endpoints, the incidence of CMV disease generally did not differ between rATG and eATG induction, and there was no significant difference between rATG and daclizumab induction with regard to the incidence of asymptomatic or symptomatic CMV infection or the proportion of patients who received treatment for a CMV episode. In other induction trials, rATG did not significantly differ from daclizumab with regard to the incidence of CMV infections that required treatment, whereas, relative to basiliximab, the incidence of CMV infection was higher with rATG in two studies, although it was lower with rATG in a study in high-risk patients. In the treatment of acute renal rejection, the nature and incidence of infections were generally similar with rATG and eATG.
The incidence of malignancies was generally low with rATG therapy, regardless of whether the drug was being administered for the prevention or treatment of renal transplant rejection, and generally did not differ from that seen with eATG, basiliximab or daclizumab. Retrospective analyses of data from three US registry databases have produced mixed findings concerning the risk of post-transplant malignancies associated with rATG and other immunosuppressive agents in renal transplant recipients.