Pharmacokinetics immunogenicity

In a study investigating the allometric relationships of pharmacokinetic parameters for five therapeutic proteins, the allometric equations for clearance and volumes of distribution, however, were found to be different for each protein [102]. This variability was attributed to possible species specificity and immune-mediated clearance mechanisms. Species specificity refers to the inherent differences in structure and activity across species. Minute differences in the amino acid sequence may render an agent inactive when administered to foreign species, and may even generate an immunogenic response. Immunogenicity has been clearly demonstrated in a study with the tumor necrosis factor receptor-immunoglobulin fusion protein lenercept. This all-human sequence protein elicits an immune response in laboratory animals which ultimately results in the rapid clearance of the protein [103]. 

A phase I/II study to evaluate the safety, immunogenicity, pharmacokinetics and potential efficacy of iv rhuTNF binding protein pegylated dimer in patients with active RA. Arthritis Rheum. 41, S58 (abstract). 

With a compound discovery method in place that achieves high potency and specificity, all that remains for aptamers to have utility as drugs would be stability, pharmacokinetics, toxicity, and low immunogenicity of aptamers in vivo. Because the literature was clear about the major human plasma endonucleases that destroy RNA molecules, one early event in the NeXstar... 

Immunogenicity is a substantial complication for preclinical safety assessment studies. Antibodies can invalidate the animal model species. Antibody production alone, however, should not necessarily prohibit the conduct of these studies. The effect on pharmacokinetics and pharmcodynamics needs to be measured and evaluated. The potential consequences of the antibodies on endogenous molecules also needs to be evaluated. Secondary effects, such as antibody deposition, should be measured. The lack of ability to predict absolute human immunogenicity does not preclude the use of animals to assess the relative potential for an immune response. 

Toxicokinetics must be assessed in preclinical toxicology studies, as with traditional pharmaceuticals. These data are necessary to prove exposure (which may differ with route) and to monitor the potential effects of antibodies on the exposure levels over time. Perhaps the greatest difference between small-molecule pharmaceuticals and large-molecule biopharmaceuticals is the potential for immunogenicity, which can greatly affect pharmacokinetics as previously discussed. 

To evaluate the biological consequences of antibodies, patients with positive responses should be monitored for their impact on the pharmacokinetic and pharmacodynamic effect of the therapeutic protein. Also the effect on adverse events and possible neutralization of the endogenous protein, in cases where human proteins are administered at pharmacological doses, should be monitored. When the consequences of the immunogenicity are known, the risk can be established. 

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