Abstract
Introduction: There is a growing interest in the minipig as a non-rodent species in the safety assessment of (bio) pharmaceuticals and (agro) chemicals. For (bio) pharmaceuticals the need to evaluate the potential adverse effects on the immune system is an increasingly important aspect of safety evaluation. In the present study, cyclosporin A and Dexamethasone were used as model compounds to examine whether the regulatory endpoints requested for immunotoxicity testing can be tested in the Gottingen minipig. Methods: Minipigs were treated with vehicle, 20 mg/kg/day cyclosporine A or 0.4 mg/kg/day dexamethasone for 39 (males) or 40 (females) consecutive days. Clinical signs, body weight, hematology, lymphocyte subset analysis in peripheral blood mononuclear cells, Natural Killer cell activity, primary and secondary antibody response and Delayed Type Hypersensitivity response against Keyhole Limpet Hemocyanin (KLH), ex vivo mitogen-induced lymphocyte proliferation, examination at necropsy for gross macroscopic changes, weights and histopathology of lymphoid organs were used as criteria for evaluation of immunotoxic effects. Results: Most parameters measured were implemented successfully in the minipig. Cyclosporin A treatment of minipigs had a slight effect on thymus weight, white blood cell counts and Keyhole Limpet Hemocyanin specific IgM responses. Clear effects were observed on mitogen-induced proliferation, Keyhole Limpet Hemocyanin specific IgG responses and Delayed Type Hypersensitivity response. Dexamethasone treatment resulted in decreased body weight, white blood cell counts, proliferative response to mitogen stimulation, Natural Killer cell activity and thymus weight. Keyhole Limpet Hemocyanin specific antibody responses were unaffected or slightly increased after dexamethasone treatment. Discussion: With few exceptions, results obtained with cyclosporine A and dexamethasone in the minipig was in accordance with those presented for other species in the literature. Overall, the results presented in this article indicate that the minipig has potential to serve as an alternative non-rodent species for immunotoxicity testing as part of the safety assessment of (bio) pharmaceuticals and chemicals.
Highlights
There is a growing interest in the minipig as a non-rodent species in the safety assessment of pharmaceuticals and chemicals
On day 13 no significant effects were observed on the number of White Blood Cells (WBC) and the differentiated WBC subsets both in the Cyclosporin A (CsA)- and DEXtreated male and female minipigs except for the increased absolute and relative (Figure 2) neutrophil numbers and the decreased relative lymphocyte numbers in CsA treated males compared to the vehicle controls
On day 27 there was a slight decrease in the number of WBC in male and female minipigs of both the CsA- and DEXtreatmentgroups
Summary
There is a growing interest in the minipig as a non-rodent species in the safety assessment of (bio) pharmaceuticals and (agro) chemicals. The ICH S8 guideline dealing with Immunotoxicity Studies for Human Pharmaceuticals [1] states that safety evaluation of human pharmaceuticals on the immune system, mainly focussed on immune suppression, should be incorporated into the standard drug development programme This should enable the prediction of unintended immunosuppression. The non-clinical safety studies to be performed to support the development of safe new drug products are outlined in ICH M3 [2] These include general toxicology, reproductive toxicology, safety pharmacology, local tolerance, genotoxicity, and immunotoxicology studies. Social and legislative resistance against the use of non-human primates is mounting These are both important reasons why the attention is increasingly focussed on the potential use of minipigs, which are likely to be a more acceptable test species to the public, as pigs are being used as a food animal [3]
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