Multiple dosing models assumptions

As with all previous PK models, multiple dosing models require a number of inherent assumptions. It turns out that the assumptions required for multiple dosing models are all derived from or identical to the assumptions already made in earlier single-dose models. 

The multiple dosing models described here represent repeated application of previously described single-dose PK models. Thus the inherent assumptions for a multiple dosing model include all the assumptions made for each of the single-dose models that are being employed. 

The superposition principle, which forms the basis of all multiple-dose models in this section, is true only as long as all elimination processes follow first-order (linear) elimination kinetics. Since the assumption of first-order elimination kinetics has already been made for all the previous single-dose models that are being combined by superposition, the application of the superposition principle does not add any new model assumptions. 

What principle forms the basis of all multiple dosing PK models in this chapter What model assumptions are required for this principle to be applicable ... 

Even the most sophisticated risk assessment has limitations. It involves numerous assumptions about both exposure and hazard. Exposure assessments typically reflect modeled concentrations or extrapolations from measured data. The degree of exposure by different individuals may vary, and their response can depend on factors such as general health, genetic predisposition, or other factors. Dose-response factors are typically extrapolated from animal studies and thus inherently introduce the imcertainty of relating the response of laboratory animals to that of humans or one of the many species in an ecosystem. The endpoints characterized may not include all of the potential effects for example, the potential for endocrine disruption has not been considered in many risk assessments and in fact standardized testing methods were not published until approximately 2007 or later [90]. And risk assessment tools only model relatively simple scenarios. They rarely account for exposure to multiple chemicals, or fully accoimt for the effects on a complex web of organisms in an ecosystem. 

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