Exposure studies dose selection

Systemic exposure of the drug candidate in the test species that represents a large multiple of human exposure, based on the plasma concentration versus time curve (AUC), at the maximum proposed human daily dose may be used for carcinogenicity study dose selection. The AUC is the most comprehensive pharmacokinetic endpoint, because this value includes both the plasma concentration of the drug candidate and the residence time in vivo. For pharmacokinetic endpoints to be used for dose selection, the information needed to establish the recommended 25-fold ratio of rodent to human normalized (using mg/m2 dose levels) AUC include that (a) rodent pharmacokinetic data are derived with the... 

This study was conducted to evaluate and compare ADD determined using whole-body dosimetry with results of two situational exposure studies conducted following use of a flea fogger under natural conditions. Chlorpy-rifos was selected due to its general availability as a fogger for indoor flea control. Chlorpyrifos is poorly absorbed by the dermal route and readily cleared from the body in urine (Nolan et al., 1984). Trichloropyridinol was measured in 24-hr urine specimens of the volunteers and was converted to chlorpyrifos equivalents as a measure of absorbed dose. The study provided an opportunity to determine the relationship between intensive, high-contact dosimetry studies and the amounts of chlorpyrifos absorbed by two sets of adults who re-entered fogger-treated homes. 

The AEGL-1 was derived from a consideration of the dose-response data, which were obtained from all of the monitoring studies and subsequently time scaled to the shorter exposure durations. Although the exposures were of chronic duration in the monitoring studies, they represent the best available human data. Symptoms observed during chronic exposures should represent the greatest potential response. An 8-h exposure duration was selected as the basis for AEGL development. 

This information may affect selection criteria for the study population and the choice of tests in addition to routine safety monitoring, and will certainly determine the starting dose, range of doses, maximum exposure and dose increments to be studied. Pharmacokinetics in man may be quite different from those in animal species so that plasma and, if possible, tissue concentrations are generally more important than dose. One exception to this may be hepatotox-icity resulting from exposure of the liver to portal blood drug concentrations, when the oral dose administered to the animals may be more relevant than the systemic plasma concentrations, which reflect first-pass metabolism as well as absorption. 

This category includes agents for which there is less than the minimum sufficient evidence necessary for assessing the potential for developmental toxicity, such as when no data are available on developmental toxicity, as well as for databases from studies in animals or humans that have a limited study design (e.g. small numbers, inappropriate dose selection/exposure information, other uncontrolled factors), or data from a single species reported to have no adverse developmental effects, or databases limited to information on structure/activity relationships, shortterm tests, pharmacokinetics, or metabolic precursors. 

The need for reproductive and developmental toxicity studies is dependent on the product, the clinical indication, and the intended patient population [50,52], Consideration is based on the nature of any expressed products and/or inappropriate biodistribution. Effects to the reproductive system that were identified in exposure and general toxicity assessments that suggest a cause for concern must be addressed in these more specific studies. If studies are necessary, study designs will likely need to be altered to accommodate selection of relevant animal model, dose selection, and dosing frequency. 

The first tolerability studies in early clinical development always provide pharmacokinetic (PK) data over a considerable dose range. Especially the explorative first-in-man study with escalating single doses, or an explorative proof of principle study with escalating multiple doses provides a valuable basis for an exploratory assessment of dose linearity/ proportionality of drugs in humans. In addition such an assessment can directly help within the same study to optimize the dose selection and dose progression. Already in this early phase of the development, these data are going to support exposure-response relationships, and thus a potential submission (US FDA 2003, ICH E4 1994). 

Ad 2) A systemic exposure representing a 25 times multiple of the human AUC (at the maximum recommended daily dose) may be an appropriate endpoint for dose selection for carcinogenicity studies for non-genotoxic pharmaceuticals, as a pragmatic solution. 

No chronic animal toxicity studies have been conducted on VX however, there are two subchronic studies which can be used for developing an RfD. In one study, rats were dosed by s.c. injection 5 days per week for 90 days (Goldman et al., 1988). In the second study, sheep received daily doses of VX in feed for 56 days (Rice et al., 1971). Both of these studies identify blood cholinesterase as the most sensitive endpoint. Data are available indicating that sheep are more sensitive than rats to the toxic effects of VX. Ivanov et al. (1993) reported that the oral LD50 in sheep is 6 figfkg whereas that for rats is 66 //g/kg. In addition, Ivanov et al. (1993) suggested that this increased susceptibihty in sheep may be due, in part, to the lower concentration of catalytic sites for serum ChE in sheep (7.098 x lO mol/L vs. 1.704 x 10 mol/L in rats). The Rice et al. (1971) study is selected here for deriving an oral RfD because it utilized an exposure route that is more relevant for an oral RfD, and also because the experimental evidence indicates that sheep are the more sensitive of the species tested. 

His thesis, for example, gives the results of a survey of sources then in current use in the German, Federal Republic, the spectral power distributions of these sources, their effect on various selected test substances as a function of time of exposure, total dose exposed to and absorbed. It is apparent from this data that the sources studied are not equivalent. 

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