Administration routes toxicity studies

Earlier studies by Wiles et al. (5) in which palytoxin was administered by various routes showed that this material was extremely toxic to rabbits, dogs, and monkeys. The effect of route of administration on toxicity varies in that intravenous (iv), intramuscular (im), and subcutaneous (sc) toxicity is high, yet intrarectal (ir) or oral (po) palytoxin is relatively ineffective. It was also observed that palytoxin... 

Absorption, Distribution, Metabolism, and Excretion. There are no data available on the absorption, distribution, metabolism, or excretion of diisopropyl methylphosphonate in humans. Limited animal data suggest that diisopropyl methylphosphonate is absorbed following oral and dermal exposure. Fat tissues do not appear to concentrate diisopropyl methylphosphonate or its metabolites to any significant extent. Nearly complete metabolism of diisopropyl methylphosphonate can be inferred based on the identification and quantification of its urinary metabolites however, at high doses the metabolism of diisopropyl methylphosphonate appears to be saturated. Animal studies have indicated that the urine is the principal excretory route for removal of diisopropyl methylphosphonate after oral and dermal administration. Because in most of the animal toxicity studies administration of diisopropyl methylphosphonate is in food, a pharmacokinetic study with the compound in food would be especially useful. It could help determine if the metabolism of diisopropyl methylphosphonate becomes saturated when given in the diet and if the levels of saturation are similar to those that result in significant adverse effects. 

The single-dose toxicity studies were performed in two mammalian species, rat and mouse, by the route used in clinical practice, that is oral, as well as that ensuring adequate systemic exposure to the drug, that is intravenous. The subacute (3 months) toxicity studies were correctly carried out in the two animal species (rat, dog) in which also the pharmacokinetics was studied. Since in accordance with the International Conference on Harmonization (CPMP/ICH/286/95), 3-month toxicity studies support clinical trials for up to 1 month s duration (the longest duration of drug administration in clinical use), chronic toxicity studies have not been performed. 

Chronic and subchronic toxicity studies are conducted to define the dose level, when given repeatedly, that cause toxicity, and the dose level that does not lead to toxic findings. In Japan, such studies are referred to as repeated-dose toxicity studies. As with single-dose studies, at least two animal species should be used, one rodent and one nonrodent (rabbit not acceptable). In rodent studies, each group should consist of at least 10 males and 10 females in nonrodent species, 3 of each sex are deemed adequate. Where interim examinations are planned, however, the numbers of animals employed should be increased accordingly. The planned route of administration in human subjects is normally explored. The duration of the study will be dictated by the planned duration of clinical use (Table 2.14). 

The physico-chemical properties may provide indications about the absorption of the substance for various routes of exposure and may therefore be of importance in the evaluation whether an appropriate administration route has been applied in the available experimental toxicity studies. In order for a substance to be absorbed, it must cross biological membranes. Most substances cross biological membranes by passive diffusion. This process requires a substance to be soluble both in lipid and water. The most useful parameters providing information on the potential for a substance to diffuse across biological membranes are the logPoctanoi/water and the water solubility. 

Toxicity studies are performed in healthy animals. Eor NCEs two species are to be used, one rodent (most often rats or mice) and one non-rodent (dog, rabbit, monkey or others). Biologies should be tested in a species in which they are pharmacologically active, usually a monkey. The route of administration is the same as that of the intended use in clinical studies. 

The September 2000 draft guidance considers excipient databases associated with drug products with three different therapeutic durations. For a drug product intended for a 14-day therapy or less, and for infrequent use, the excipient should be tested in acute toxicity studies and in one-month, repeat-dose toxicity studies in two mammalian species (one being a nonrodent), using the intended route of therapeutic administration. 

Prior to the initiation of chronic toxicity studies, there should be characterization of test chemical. Information on chemical identity and structure can sometimes be used in an analysis based on structure activity relationships to indicate biological or toxicologic activity. The physical and chemical characteristics of the test chemical provide important information for the selection of administration routes, study design, and handling and storage of the test chemical. 

Beta-cyclodextrin has been the most studied of the cydodextrins. Results from numerous investigations have demonstrated its safety and metabolism. Table 22.4 shows the results of acute toxicity studies from various routes of administration. At the maximum dose of (3-cyclodextrin presented orally, no mortality related to it was... 

Multiple time points are included in study designs to assess acute and late effects as well as the reversibility of any adverse effects. The route of administration should reflect the intended clinical use. Repeated-dose toxicity studies are only relevant if the clinical use includes multiple dosing. For example, in the case of p pancreatic islet cells, toxicity studies should mimic the clinical scenario of retransplantation assessment of acute toxicities and cumulative effects that would preclude retransplantation. 

Acute toxicity studies. Tabulate species, sex, age, dose range, pharmacologic actions and interactions with other drugs, routes of administration, vehicle, toxic signs, lethal dose, time of death, etc. 

Multidose toxicity studies (subchronic, carcinogenicity, pharmacologic, and interactions with other drugs). Provide a table of studies including species and strain, number of animals, sex, age, dose, dose schedule, and route of administration. Notable treatment and dose-related changes in survival, per-... 

Nonclinical PK/T V The pharmacokinetic profile of Fortical by different routes of administration was compared to Miacalcin, demonstrating similarity in PK profiles between the synthetic and recombinant peptides and toxicity results (28-day rat intranasal toxicity study) were acceptable, particularly in light of clinical safety data. 

The principal study is a well-designed and well-conducted reproductive toxicity study in rats. The identified endpoint (gastric lesions), also identified in a subchronic study and in two developmental studies, supports the conclusion that direct contact with epithelial tissue is the primary mechanism of toxicity. However, the principal study did not identify a NOAEL for this effect and the route of administration (gavage) may have led to an enhanced response due to the bolus type of dosing. Consequently, the overall confidence in the RfD must be considered medium. 

It is preferable that animal studies are conducted using appropriate routes of administration which relate to the potential route of human exposure. However, in practice, reproductive toxicity studies are commonly conducted using the oral route, and such studies will normally be suitable for evaluating the hazardous properties of the substance with respect to reproductive toxicity. However, if it can be conclusively demonstrated that the clearly identified mechanism or mode of action has no relevance for humans or when the toxicokinetic differences are so marked that it is certain that the hazardous property will not be expressed in humans then a substance which produces an adverse effect on reproduction in experimental animals should not be classified. 

Acute toxicity studies may be conducted by administering the drug by any of several routes (oral, intravenous, intramuscular, intraperitoneal, subcutaneous, or dermal). The route chosen usually is that intended to be used clinically. Rats and mice are generally used for acute toxicity work however, rabbits are commonly used when the route of administration is dermal. 

Animal toxicology a summary along with acute, long-term, reproduction, local toxicity and mutagenic/carcinogenic data. There are detailed requirements of toxicity studies in terms of time, dose, route of administration, which are beyond the scope of this article. Reproduction study requirements are also specified in terms of fertility studies, terato-genecity studies and perinatal studies. Local toxicity is limited to preparations intended for topical use. 

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