Multiple -dose toxicity duration

Traditionally, the duration of a toxicity study depends on the intended clinical use and disease duration. The potential immunogenicity of the human protein is a significant issue since antibody binding can partially or completely inhibit the biological activity of that protein, affect its catabolism or alter its distribution and clearance. Any multiple-dose study therefore should include evaluation of the impact of antibody formation, including their neutralizing capacity. However, antibody formation in itself should not be a reason for termination of a toxicity study, particularly if the antibodies are not neutralizing or do not alter the pharmacodynamics of the protein. 

Ethanol Multiple effects on neurotransmitter receptors, ion channels, and signaling pathways Antidote in methanol and ethylene glycol poisoning Zero-order metabolism duration depends on dose Toxicity Acutely, CNS depression and respiratory failure chronically, damage to many systems, including liver, pancreas, GI tract, and central and peripheral nervous systems Interactions Induces CYP2E1 Increased conversion of acetaminophen to toxic metabolite... 

Single and repeat dose toxicity studies (with later mainly in the rat and dog by oral or intravenous route and up to 1 year duration), reproduction toxicity (embryo-foetal studies in the rat and rabbit), battery of genotoxicity assays, carcinogenicity studies (by diet route in mouse and rat) plus ADME studies (single and multiple dosing)... 

Rocuronium (Fig. 16.21) preserves the vecuronium trend of tertiary versus quaternary nitrogens, but with further modifications on the nitrogen substitutes. The dmg has a similar pharmacokinetic, duration of action, and toxicity profile to vecuronium but six times less potent. It has a fast onset of action (about 2 minutes). Recuronium is supplied as its bromide salt in multiple-dose vials containing volumes of 50 or 100 mL at a concentration of 10 mg/mL. 

Several studies provided evidence of CDD-related carcinogenicity in animals. In general, the effects were dependent on the congener, species, sex, and route of administration, and were seen at doses that were close to doses that are toxic in the same animal species. Intermediate- and chronic-duration oral exposure to 2,3,7,8-TCDD induced multiple-site carcinomas and/or sarcomas in rats (Kociba et al. 

The initial process in the application of toxicity (dose-response) data in risk assessment is the extrapolation of findings to establish acceptable levels (AL) of human exposure. These levels may be reference values (inhalation reference concentrations, RfC or oral reference doses, RfD), minimal risk levels (MRL) values, occupational exposure limits, and so on. When the toxicity data are derived from animals, the lowest dose representing the NOAEL (preferably) or the LOAEL defines the point of departure (POD). In setting human RfD, RfC, or MRL values, the POD requires several extrapolations (see [13] and revisions). Extrapolations are often made for interspecies differences, intraspecies variability, duration of exposure, and effect level. Each area is generally addressed by applying a respective uncertainty factor having a default value of 10 their multiplicative value is called the composite uncertainty factor (UF). The UF is mathematically combined with the dose at the POD to determine the reference value ... 

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