Biopharmaceutics studies animal models

In-vitro models can provide preliminary insights into some pharmacodynamic aspects. For example, cultured Caco 2 cell lines (derived from a human colorectal carcinoma) may be used to simulate intestinal absorption behaviour, while cultured hepatic cell lines are available for metabolic studies. However, a comprehensive understanding of the pharmacokinetic effects vfill require the use of in-vivo animal studies, where the drug levels in various tissues can be measured after different dosages and time intervals. Radioactively labelled drugs (carbon-14) may be used to facilitate detection. Animal model studies of human biopharmaceutical products may be compromised by immune responses that would not be expected when actually treating human subjects. 

As is true for all biopharmaceuticals, toxicity studies should be performed in relevant animal models. For cellular therapies these models are often in animal models intended to mimic the human disease. When possible the intended human cells are utilized for assessments with or without low-dose immunosuppressants (e.g., lOmg/kg, i.p. dose of cyclosporine A in rats). The immunosuppressive drug is generally administered prior to the cell dose and extended for a specified period after the transplant. In cases where it is not feasible to use the intended clinical material, largely due to the inability of the cells to engraft sufficiently into the host, analogous cells can be used to assess preclinical safety and activity. In such cases it is important to understand the potential impact of any differences between the analogous product and the clinical product in order to improve extrapolation of safe and active cell doses to humans. 

For brevity, only the pivotal toxicology studies are given. Examples of studies not included are proof-of-concept, comparability, toxicokinetic, pharmacokinetic, pharmacodynamic, local tolerance, and miscellaneous in vitro and in vivo studies. Pharmacokinetic and pharmacodynamic experiments generally used the pivotal toxicology animal model(s) because of the species specificity of the biopharmaceutical. 

A more relevant study for biopharmaceuticals is the repeat-dose study where exaggerated clinical doses are given to an animal model using the intended clinical route of administration. For most biopharmaceuticals this is the intravenous route of administration. Interesting exceptions are Lucentis and Pulmozyme , given intraocularly and by inhalation, respectively, in the pivotal repeat-dose studies. 

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