Hypersensitivities immunogenicity

A rare but serious event that can result from irreversible CYP inhibition is the development of a hypersensitivity reaction. The bioactivation of a drug and the formation of a covalent adduct between the activated substrate and the enzyme can lead to hapten formation and eventually to an idiosyncratic autoimmune response (usually in the form of autoimmune hepatitis) [14]. The hapten formation is the first key step toward the autoimmune response. The CYP macromolecule is made immunogenic ( foreign ) by the covalent binding of the electrophilic metabolites, and the immune reaction follows with the production of autoantibodies against the target molecule (not necessarily alkylated). 

Re-administration might be an issue for abciximab, due to its inherent immunogenicity. Human antichimeric antibody is detectable in about 5% to 6% patients receiving abciximab therapy, but no antibodies have been observed in response to the small molecules. In practice, re-administration registry of 500 patients showed similar safety and efficacy for repeat administration when compared with first time administration (80). No reports of hypersensitivity or anaphylactic reactions were reported with abciximab re-administration. Thus, these agents can be safely re-administered with careful monitoring of platelet counts, especially with abciximab therapy. 

Immunogenicity Rare allergic or hypersensitivity reactions may occur Common may affect PK or result in immune-mediated adverse events other than allergic and/or hypersensitivity responses... 

A variety of assays have been designed and validated to measure specific antibodies in the sera of treated animals. In addition efforts have been paid to minimizing the immunogenicity of therapeutic proteins. As these issues are addressed comprehensively in another chapter of this volume, the focus here will be on predicting problems that may ensue from the presence of such antibodies, namely hypersensitivity reactions. Presumably because allergic reactions have long been considered to be nonreproducible in animal models, limited efforts have been paid to designing predictive animal models until recently. Unexpectedly, the consequence is that no adequately standardized and validated model is available at the present time. 

Clavulanic acid has a very low immunogenic and allergenic potential in animals. The possible impact of its co-administration with other beta-lactam antibiotics is unknown (53). Two patients with IgE-mediated hypersensitivity to oral co-amoxiclav and positive skin tests for clavulanic acid, but not for penicillins, both tolerated oral amoxicillin. One patient was also challenged with clavulanic acid and developed urticaria, conjunctivitis, and bronchial obstruction (54). Since co-amoxiclav has been widely used since its introduction in 1981, the frequency of hypersensitivity reactions is low. The clinical data available on sulbactam and tazobactam are stiU hm-ited and do not allow an assessment of the frequency and pattern of associated hypersensitivity reactions (55). 

An immunogen is either a protein or a substance coupled to a carrier, usually a protein, that when introduced into a foreign host is capable of inducing the formation of an antibody in the host. The route of introduction of the immunogen is usually, but not always, intradermal. The antibody produced may be either circulating (humoral) or tissue bound (cellular), as in delayed hypersensitivity reactions or graft host reactions. 

Immunogenicity is undesirable because it can be the source of a number of safety concerns, such as hypersensitivity and allergic reactions, thrombocytopenia, anemia, etc. Very problematic with recombinant therapeutic proteins, but fortunately extremely unlikely with antibodies, are... 

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