Pharmacodynamic-based toxic effects

Pharmacodynamic-based toxic effects are those where there is altered responsiveness of the target site perhaps due to variations in the receptor. For example, individual variation in the response to digitoxin means that some patients suffer toxic effects after a therapeutic dose (see below Chapter 7). The inhibition of enzymes, blockade of receptors or changes in membrane permeability which underlie these types of effects often rely on reversible interactions. These are dependent on the concentration of the toxic compound at the site of action, and possibly the concentration of an endogenous substrate if competitive inhibition is involved. Therefore, with the loss of the toxic compound from the body, by the processes of metabolism and excretion, the concentration at the site of action falls and the normal function of the receptor or enzyme returns. This is in direct contrast to the type of toxic effect in which a cellular structure or macromolecule is permanently damaged, altered or destroyed by a toxic compound. In some cases, however, irreversible inhibition of an enzyme may occur, which if not fatal for the organism will require the synthesis of new enzyme, as is the case with organophosphorus compounds which inhibit cholinesterases. 

Two distinct bases for these types of effects may be distinguished pharmacokinetic and pharmacodynamic. Pharmacokinetic-based toxic effects are due to an increase in the concentration of the compound or active metabolite at the target site. This may be due to an increase in the dose, altered metabolism or saturation of elimination processes for example. An example is the increased hypotensive effect of debrisoquine in poor metabolizers where there is a genetic basis for a reduction in metabolic clearance of the drug (see Chapter 5). 

Adverse effects can be based on the pharmacodynamics of the drug i.e. side effects (occur at therapeutic dose of the drug), toxic effects (occurs at overdose or poisoning) and drug withdrawal symptoms (i.e. 

Physiologically Based Pharmacodynamic (PBPD) Model—A type of physiologically-based dose-response model which quantitatively describes the relationship between target tissue dose and toxic end points. These models advance the importance of physiologically based models in that they clearly describe the biological effect (response) produced by the system following exposure to an exogenous substance. 

Doses selected for safety pharmacology studies are typically based on the criteria established in the ICH S7A guidance.25 Doses should exceed those projected for clinical efficacy and at the upper limit be bound by (1) adverse pharmacodynamic effects in the safety pharmacology study (2) moderately adverse effects in other non-clinical studies that follow a similar route and duration of dosing or (3) limit of solubility/toxicity. In the absence of adverse effects, the maximum administrable dose can be used. If nonreusable animals enter the study, then the maximum tolerated dose may be appropriate. Most importantly, the doses/concentrations should establish the dose/concentration-response relationship of the adverse effect. 

The ICH S7A guidance states that "supplemental" studies are meant to evaluate potential adverse pharmacodynamic effects on organ systems functions that are not acutely essential for the maintenance of human life and not addressed by the "core battery" or repeated dose toxicity studies when there is a cause for concern.25 Examples of physiological functions that fall into that category include, but are not limited to, the renal/urinary, immune, GI, endocrine and autonomic nervous systems. This section focuses on the renal and GI systems based on their potential impact on the clinical development program. 

When a model (e.g., concentration addition or response addition) is considered appropriate for describing the mixture effects observed in experiments, it can serve predictive purposes (such as formulating a scientific null hypothesis for an experiment), or for practical extrapolation and for risk assessment. There are, however, limitations associated with the concepts and the associated models based on pharmacodynamic reasoning. These limitations were first recognized by Plackett and Hewlett (1952), yet have mainly gone unnoticed by followers of the mechanistic school of mixture toxicity. Three main limitations are identified, and extrapolation solutions are provided. 

The UEL for reproductive and developmental toxicity is derived by applying uncertainty factors to the NOAEL, LOAEL, or BMDL. To calculate the UEL, the selected UF is divided into the NOAEL, LOAEL, or BMDL for the critical effect in the most appropriate or sensitive mammalian species. This approach is similar to the one used to derive the acute and chronic reference doses (RfD) or Acceptable Daily Intake (ADI) except that it is specific for reproductive and developmental effects and is derived specifically for the exposure duration of concern in the human. The evaluative process uses the UEL both to avoid the connotation that it is the RfD or reference concentration (RfC) value derived by EPA or the ADI derived for food additives by the Food and Drug Administration, both of which consider all types of noncancer toxicity data. Other approaches for more quantitative dose-response evaluations can be used when sufficient data are available. When more extensive data are available (for example, on pharmacokinetics, mechanisms, or biological markers of exposure and effect), one might use more sophisticated quantitative modeling approaches (e.g., a physiologically based pharmacokinetic or pharmacodynamic model) to estimate low levels of risk. Unfortunately, the data sets required for such modeling are rare. 

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