Clinical Frame of Reference Related to ADRs

Two or more drugs administered in therapeutic concentrations at the same time or in close sequence may act independently, may interact to increase or diminish the effect of one or more drugs, or may act to cause an unintended effect. All “on-target,” “off-target,” and cytotoxic ADRs have a pharmacokinetic or a pharmacodynamic basis and include those ADRs which, with the exception of overdose, are precipitated by drug-drug, drug-food, drug-herbal, and drug-disease interactions with therapeutic doses of a drug.6

The risk of ADRs depends on the margin of safety between the dose of a drug required for efficacy and the dose that causes ADRs.6 When the margin of safety is large, ADRs result primarily from overdose; when the margin of safety is small, ADRs may manifest at therapeutic doses. In addition to the dosage of the drug administered and drug-drug, drug-food, drug-herbal, and drug-disease interactions the margin of safety is also modulated by other patient-related variable such as genetic determinants and age.6