Pharmaceuticals exposure routes

In the pharmaceutical industry, the two most common routes of administration are via diet and gavage (PMA, 1988). Some compounds are given by drinking water, topical (dermal) application, or injection, depending on the expected clinical exposure route, which is the primary criterion for determining the route of administration in carcinogenicity studies. When more than one clinical route is anticipated for a drug, the dietary route is often chosen for practical reasons. 

EXPOSURE ROUTES Inhalation (contaminated air and tobacco smoke), ingestion (fried chicken, mountain cheese and fish), absorption (pharmaceuticals) occupational exposure. 

EXPOSURE ROUTES occupational exposure in dye manufacturing industry and the pharmaceutical industry ingestion drinking water... 

The dying vultures illustrated a short and direct route between pharmaceutical exposure and harm to a wild animal. Kolpin s research, on the other hand, presents an exposure route from waste-water to aquatic organism that is more diffuse and occurs at lower concentrations. Is there evidence that exposures such as these represent a serious threat to aquatic wildlife such as fishi ... 

Poly(ethylene oxide) resins are safely used in numerous pharmaceutical and personal-care appHcations. Poly(ethylene oxide) resins show a low order toxicity in animal studies by all routes of exposure. Because of their high molecular weight, they are poorly adsorbed from the gastrointestinal tract and completely... 

The formulations that are developed and used for preclinical studies are sometimes specific for the test species to be employed, but their development always starts with consideration of the route of exposure that is to be used clinically and, if possible, in accordance with a specified regimen of treatment (mirroring the intended clinical protocol, as much as possible). One aspect of both nonclinical and clinical formulation and testing which presents an important but often overlooked aspect of pharmaceutical safety assessment is the special field of excipients. These will be considered at the end of this chapter... 

The other main route used for pharmaceutical preparations is inhalation using a head only exposure system. Parenteral administration, although technically possible, is usually avoided because of the local irritant effects that can occur with repeated injection, particularly by the subcutaneous route. Topical administration is an option for materials intended for administration to the skin. 

The treatment route is chosen according to the intended route for the clinical use of the pharmaceutical or the main anticipated route of human exposure for chemicals. 

The U.S. FDA states in the Guidance for Nonclinical Studies for Development of Pharmaceutical Excipients (2) that they will continue to consider factors such as use in previously approved products, GRAS-status, or a food additive to evaluate the safety of a new excipient. The FDA states . .. an excipient with documented prior human exposure under circumstances relevant to the proposed use may not require evaluation in a full battery of toxicology studies... FDA also states under some circumstances (e.g., similar route of administration, level of exposure, patient population, and duration of exposure) other factors can adequately qualify an excipient (2). The sponsor of a new excipient should meet with the FDA to provide information regarding the toxicology, chemistry, manufacturing, and controls necessary to evaluate a potential new excipient. 

Inhalation and direct skin contact are the most common routes of chemical exposure. The greatest exposure risk in handling potent compounds in an analytical laboratory therefore occurs when handling solid materials due to the potential to generate and inhale airborne dust particles of the compound. Once the potent material has been placed into solution, the airborne exposure risk is reduced and solutions of potent compounds may be handled in a manner similar to other nonpotent pharmaceutical compounds, assuming good laboratory practices are followed. Caution should be taken not to aerosolize the solutions since this could create an inhalation hazard. In addition, any sample solution spills should be adequately cleaned to prevent powder deposits of the compound from forming, which could potentially become airborne after the liquid has dried. 

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. 

Pharmaceuticals apphed topically (e.g., dermal and ocular routes of administration) if knowledge is already available from systemic exposure further local testing may not be necessary unless concentration or duration are very prolonged... 

Pharmaceuticals showing poor systemic exposure from topical route... 

Pharmaceuticals administered by ocular route unless cause for concern or unless there is significant systemic exposure... 

Pharmaceuticals showing poor systemic exposure from topical routes in humans may not need studies by the oral route to assess the carcinogenic potential to internal organs. 

The route of administration of the test compound should ensure a relevant target exposure and in the case of pharmaceuticals it should consider the application route in humans. Each treated and control group must include at least 5 animals that can be analyzed per sex. It is possible to use only one gender if it can be demonstrated that no substantial differences in metabolism,... 

Oral administration is the most popular route due to ease of ingestion, pain avoidance, versatility, (to accommodate various types of dmg candidates), and, most importantly, patient compliance [119]. In addition, solid oral delivery systems do not require sterile conditions and are, therefore, less expensive to manufacture. Orally delivered pharmacologically active compounds must have favorable absorption and clearance properties, and satisfactory metabolic stability to provide adequate systemic exposure to elicit a pharmacodynamic response. If the compounds possess reasonable physicochemical properties have low to intermediate clearance and reasonable absorption, adequate oral bioavailabdity may be achieved [120]. Indeed, oral bioavailability, defined as the rate and extent to which the active dmg is absorbed from a pharmaceutical form and becomes available at the site of dmg action [121], is influenced by several factors including solubility, permeability, intestinal and liver metabolism, rapid biliary and other efflux pump-mediated excretion, and conditions in the gastrointestinal milieu [122,123]. Thus, both absorption and elimination processes determine the oral bioavailability F of a given dmg. Accordingly, F can be estimated as... 

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