Source: Health Products Regulatory Authority (IE) Revision Year: 2022 Publisher: Neovii Biotech GmbH, Am Haag 6+7, 82166 Graefelfing, Germany
Pharmacotherapeutic group: immunosuppressive drug, immunoglobulin against human T lymphocytes (rabbit)
ATC code: L04AA04
Grafalon is a high-titre anti-T-lymphocyte immunoglobulin preparation with immunosuppressive activity.
Grafalon is isolated from the serum of rabbits previously immunised with human T-lymphoblasts from the human Jurkat cell line. Grafalon as polyclonal anti-T-lymphocyte antibody solution is described to have a direct effect on T-lymphocyte, thus resulting in a T-lymphocyte depletion after administration.
Among other effects published results of in vivo and in vitro tests indicate that the effect of Grafalon is due to the binding to CD2+, CD3+, CD4+/CD28+, CD5+, CD7+, LFA-1+, and ICAM-1+ lymphocytes. Mainly T-lymphocytes express these surface markers.
Multiple reports regarding the use of Grafalon 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 those 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.
Grafalon is administered by the intravenous route and therefore is 100 % bioavailable.
Pharmacokinetic studies showed that during intravenous administration of 4 mg/kg BW/d (for 7 days) Grafalon serum levels increased from 48 ± 5 microgram/ml on day 1 to 204 ± 13 microgram/ml on day 7 with a half-life of approximately 14 days after the last dose. However, the serum level of Grafalon does not correlate with its immunosuppressive activity. Grafalon is subject to protein metabolism as are other body proteins.
After intravenous administration of 900 mg/kg BW in rabbits, the animals demonstrated no pathological changes in either the clinical picture or in the haematological test results.
With a dosage of 100 mg/kg BW in the rhesus monkey, only in the first 3 days a slight motory inhibition, a shift in the neutrophilic granulocytes in the haemogram and a temporary decrease of the reticulocytes and thrombocytes were observed.
The determination of the sub-acute (chronic) toxicity was performed on the rhesus monkey. The intravenous application of 300 and 500 mg/kg BW/day lead on the 7th day (300 mg) and on the 5th day (500 mg) to the death of the experimental animals. The toxic symptoms indicate an anaphylactic shock with circulatory collapse as the cause of death.
In comparison to the control group, there was a decreasing lymphocyte count in all dosage groups. The histological findings and the other haematological findings lay within the normal range. An activation of the lymphatic organs could not be determined in any of the experimental animals.
An influence on the CNS through the administration of Grafalon can be excluded by the results of the trials on the conscious cat.
The trials on the anaesthetised cat gave no indications of cardiovascular side-effects.
Furthermore, Grafalon showed no mutagenic effect in 3 different in vitro-test, both with and without metabolic activation.
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