Dose-exposure-response relationship

Dose (exposure)-response relationship Characterization of the relationship between administered dose or exposure and the biological change in organisms. It may be expressed as the severity of an effect in one organism (or part of an organism) or as the proportion of a population exposed to a chemical that shows a specific reaction. 

Aim Quantitative description of the dose-exposure-response relationship Mechanism-based description of the processes underlying the dose-response relationship... 

Uncertainty Factors/Rationale Total uncertainty factor 30 Interspecies 10—The 10-min LC50 value for the monkey was about 60% of the rat value and one-third the rabbit value. The mouse data were used to calculate the AEGL levels, because the data exhibited a good exposure-response relationship and the endpoint of decreased hematocrit levels can be considered a sensitive indicator of arsine toxicity. In addition, arsine has an extremely steep dose-response relationship, allowing little margin in exposure between no effects and lethality. 

Drugs with very low aqueous solubility usually have sizeable inter- and/or intrasubject variability in their pharmacokinetics, which makes the study design and conduct of Phase I studies very challenging, makes the assessment of dose-response and exposure-response relationships more difLcult, and makes the dose recommendation and optimization less feasible for NDA and product labeling. 

Another option attempts to convert biomonitoring results into a form that is directly useful for risk assessment. The chapter describes both the human pharmacokinetic (PK) modeling used to relate internal concentration to dose and the development of exposure-response relationships in animal studies that use biomarker concentrations rather than applied dose (see Figure 5-2c). Finally, the chapter describes how biomonitoring studies can augment and help to interpret traditional risk assessments. 

The therapeutic administration of biologic hormones should, ideally, mimic the endogenous secretion patterns of the hormone to achieve optimal effects. Hormone formulations and dosing regimens have been developed to reflect the normal time-course of exposure to the hormone. In some cases, the effects of the hormone can be highly dependent on the dose schedule. These important aspects of the exposure-response relationships for hormones are illustrated here for insulin and parathyroid hormone. 

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). 

Another difficulty arises from the use of cumulative exposure (the product of exposure duration x intensity) as a surrogate exposure metric in the available studies. Finkelstein (1995) noted that the use of cumulative exposure requires the assumption that duration and intensity are equally important in determining the effective dose. Finkelstein further noted that if exposure estimates are inaccurate or inconsistently measured (which can be the case for many retrospective epidemiology studies), a finding of a statistically significant association between cumulative exposure and a health outcome can mislead one in having confidence in an apparent exposure-response relationship that is principally influenced by duration of exposure and not by exposure intensity. 

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