Rabbit anti-human thymocyte globulin is a selective immunosuppressive agent (mostly acting on T lymphocytes). Lymphocyte depletion probably constitutes the primary mechanism of the immunosuppression induced by rabbit anti-human thymocyte globulin. This depletion is both peripheral and central; peripheral lymphocyte depletion can be detected as early as 24 hours after the first infusion. Lymphocyte counts start to rise as soon as antithymocyte immunoglobulin is discontinued.
This lymphocyte depletion has been shown to occur in vitro by a number of different mechanisms (eg apoptosis, complement dependent lysis and antibody dependent cytotoxicity); the exact mechanisms which take place in vivo remain undetermined.
In addition to the T cell depletion, antithymocyte immunoglobulin also has effects on dendritic cells (causing apoptosis), and on B cells. In vitro, antithymocyte immunoglobulin does not activate B-cells. Antiproliferative activity against B-cells and certain lymphoblastoid cell lines has also been demonstrated in vitro. This effect may be partially protective against the development of PTLD.
Antithymocyte immunoglobulin also has activity against a number of cell surface epitopes (e.g. CD3, CD7, CD8, CD19, CD20, CD32, CD28), binding to them and causing downmodulation. The epitopes targeted include those involved in the immune response, in apoptosis, and in signal transduction, and include both B and T cell epitopes. In particular, antithymocyte immunoglobulin has activity against both leucocyte and endothelial cell adhesion molecules (e.g. CD11a, CD18, CD11b, CD44, CD54, LPAM 1) which in animal studies has been shown to reduce tethering of leucocytes to the endothelium. Effector cells are thus unable to migrate through the endothelium to the graft. This effect may also, in theory, reduce ischaemia-reperfusion injury by allowing better flow through the microcirculation.
The combination of T cell depletion and down modulation of adhesion molecules results in interference with multiple pathways by which rejection occurs.
Multiple reports regarding the use of antithymocyte immunoglobulin in children have been published. These reports reflect the broad clinical experience with this product in paediatric patients and suggest that the safety and efficacy profiles in paediatric patients are not fundamentally different to that seen in adults.
However, there is no clear consensus with regards to the dosing in paediatrics. As in adults, the posology in paediatrics depends on the indication, the administration regimen, and the combination with other immunosuppressive agents. This should be considered by physicians before deciding on the appropriate dosage in paediatrics.
Following the first infusion of 1.25 mg/kg of antithymocyte immunoglobulin (in kidney transplant recipients), total serum rabbit IgG levels of between 10 and 40 µg/ml are obtained. The serum levels decline steadily until the following infusion with an estimated elimination half-life of 2-3 days. There has been shown to be a relationship between dose given and total antithymocyte immunoglobulin levels.
The trough rabbit IgG levels increase progressively reaching 20 to 170 µg/ml at the end of an 11-day course of treatment. A gradual decline is subsequently observed following discontinuation of treatment with rabbit anti-human thymocyte globulin. However, total rabbit IgG remains detectable in 81% of patients at 2 months. Active antithymocyte immunoglobulin (that is IgG which is available to bind to human lymphocytes and which causes the desired immunological effects) has a less noticeable relationship with dose given, and disappears from the circulation faster, with only 12% of patients having detectable active antithymocyte immunoglobulin levels at day 90.
Significant immunisation against rabbit IgG is observed in about 40% of patients. In most cases, immunisation develops within the first 15 days of treatment initiation. Patients presenting with immunisation show a faster decline in total but not active rabbit IgG levels.
No mutagenicity, reproduction or genotoxicity studies have been conducted due to the nature and intended use of the medicinal product.
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