Toxicity studies

Toxicity studies are carried out on all putative new drugs, largely via testing in animals, in order to ascertain whether the product exhibits any short-term or long-term toxicity.

Acute toxicity is usually assessed by administration of a single high dose of the test drug to rodents. Both rats and mice (male and female) are usually employed. The test material is administered by two means, one of which should represent the proposed therapeutic method

Target cell

Biopharmaceutical

Target cell

Examples:

Hormones Cytokines

Target molecule ►

Biopharmaceutical

Biopharmaceutical t

Examples:

Macugen (Chapter14) Enbrel(Chapter 9) Therapeutic antibodies

Figure 4.8 Overview of the mode of action of a biopharmaceutical. Some initiate their therapeutic effect by binding to a specific cell surface receptor, with subsequent signal transduction triggering the initiation of an intracellular response (e.g. activation of an intracellular enzyme or alteration of gene expression) (a). Other biopharmaceuticals function by binding to (and thus usually inactivating) a target molecule, perhaps whose overexpression is causing/exacerbating a medical condition (b). Therapeutic enzymes function by catalysing the conversion of specific target substrate molecule(s) into a product (c)

Figure 4.8 Overview of the mode of action of a biopharmaceutical. Some initiate their therapeutic effect by binding to a specific cell surface receptor, with subsequent signal transduction triggering the initiation of an intracellular response (e.g. activation of an intracellular enzyme or alteration of gene expression) (a). Other biopharmaceuticals function by binding to (and thus usually inactivating) a target molecule, perhaps whose overexpression is causing/exacerbating a medical condition (b). Therapeutic enzymes function by catalysing the conversion of specific target substrate molecule(s) into a product (c)

of administration. The animals are then monitored for 7-14 days, with all fatalities undergoing extensive post-mortem analysis.

Earlier studies demanded calculation of an LD50 value (i.e. the quantity of the drug required to cause death of 50 per cent of the test animals). Such studies required large quantities of animals, were expensive, and attracted much attention from animal welfare groups. Its physiological relevance to humans was often also questioned. Nowadays, in most world regions, calculation of the approximate lethal dose is sufficient.

Chronic toxicity studies also require large numbers of animals and, in some instances, can last for up to 2 years. Most chronic toxicity studies demand daily administration of the test drug (parenterally for most biopharmaceuticals). Studies lasting 1-4 weeks are initially carried out in order to, for example, assess drug levels required to induce an observable toxic effect. The main studies are then initiated and generally involve administration of the drug at three different dosage levels. The highest level should ideally induce a mild but observable toxic effect, whereas the lowest level should not induce any ill effects. The studies are normally carried out in two different species, usually rats and dogs, and using both males and females. All animals are subjected to routine clinical examination, and periodic analyses of, for example, blood and urine are undertaken. Extensive pathological examination of all animals is undertaken at the end of the study.

The duration of such toxicity tests varies. In the USA, the FDA usually recommends a period of up to 2 years, whereas in Europe the recommended duration is usually much shorter. Chronic toxicity studies of biopharmaceuticals can also be complicated by their likely stimulation of an immune response in the recipient animals. In the context of new chemical entities (NCEs, i.e. low molecular weight traditional chemicals), not only can the drug itself exhibit a toxic effect, but so potentially can drug breakdown products. As proteins are degraded to amino acids, any potentially toxicity associated with protein-based drugs is typically associated with the protein itself and not degradation products.

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