Toxicology formulation-associated

A classic technique employed in pharmacology and toxicology disposition studies for all routes of administration is the mass balance approach (Riviere, 1999). Mass balance analysis accounts for all of the topically applied dose of the compound, whether it is in the formulation, associated with the skin surface, penetrated into the stratum comeum, distributed into the carcass, or absorbed into and excreted from the blood into urine and feces. In this context, total recovery of 90% of the apphed dose is considered excellent recovery (Schaefer and Redelmeier, 1996). Mass balance studies are conducted by collecting all excreta after topical and parenteral administration. Data from a parenteral route such as intravenous dosing is required to correct for the fraction of absorbed compoimd appearing into the excreta collected if a precise estimate of bioavailability is to be determined and all routes of excretion are not collected (e.g., collection of urine and feces but not expired air) (Riviere, 1999). In such a study, absorption is calculated as follows ... 

The Drug Substance Before starting any long-term toxicological studies in rodent (rat or mouse) and nonrodent (dog or monkey) species, it is imperative to work out all the chemical, pharmaceutical, large-scale synthesis, purification, stability, and formulation issues associated with the dmg substance (Smith et al., 1996 van De Waterbeemd et al., 2001). 

Central to the issues of quality, transparency, and domain identification as they relate to toxicological QSAR is biological data. High quality toxicity data on a structurally diverse set of molecules are required to formulate and validate high quality QSARs. Quality toxicity data typically come from standardized assays measured in a consistent manner, with a clear and unambiguous endpoint, and low experimental error. In such cases, quality is associated with values, which are accurate, consistent with other data within the same set, and consistent with data for other similar endpoints. In the case of comparisons between endpoints, it is as important for data to be consistent between endpoints as for the inconsistencies to be consistent. 

The question of pesticide residues and their environmental implications must be considered in the context of the active ingredient and its accompanying trace materials. The lUPAC definition of a pesticide residue is "any substance or mixture of substances in or on any substrate resulting from the use of a pesticide and includes any derivatives, such as degradation and conversion products, metabolites, reaction products and impurities (11). The significance of that residue depends on the toxicological properties of the substance and the degree of exposure. Thus, by definition, materials associated with the pesticide in the formulation must necessarily be considered as "pesticide residues". 

Absolute bioavailability is a measure of the true extent of systemic absorption of an extravascularly administrated drug. Along with clearance and volume of distribution, absolute bioavailability is one of the important parameters to characterize PK. Low bioavailability of a drug can be caused by incomplete dissolution when administrated as a solid, inability to permeate membranes, and metabolic instability (first-pass metabolism). Despite the importance of absolute bioavailability, it is not routinely assessed due to the cost and toxicology requirements for such a study in a conventional study design, which requires an intravenous reference. Safety issues may arise due to solubility limitation and toxicity associated with Cmax effect. As a result, it is necessary to conduct a preclinical toxicological study with an IV formulation to ensure adequate human safety and potential problem. Bioavailability determined from animal models is not always predictive of that in human. 

The safety-toxicological testing of a new excipient for Europe or the United States is as extensive as that for an NCE and can take four to five years to complete. There are differences in the safety evaluation requirements for different types of formulations oral, parenteral and topical/transdermal. The International Pharmaceutical Excipients Council (IPEC Europe and IPEC-Americas) have been working on a protocol for the rational safety testing of excipients to aid the introduction of new chemical excipients (see Table 5.4). IPEC is a federation of three independent regional industry associations based in Europe, the United States and Japan who are focused on the applicable law, regulations and business practices of each region with respect to pharmaceutical excipients. 

The final stage of optimisation will normally involve generating sufficient stability data on one or more variants to select the best variant. The optimal product will usually be selected based on technical merit. However, there may be a need to consider other factors, such as the use of novel excipients and the associated safety/toxicological implications, supplier and sourcing issues or the ability to patent the formulation or not. Some of these issues are discussed further below. 

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