Experimental methods

Basic principles

Overall, it is much easier to assess and quantify pharmacokinetic interactions than pharmacodynamic ones. In the case of pharmacokinetic interactions, one drug will alter the pharmacokinetics of another drug. Changes in pharmacokinetic parameters can be assessed quantitatively by single dose pharmacokinetic studies, by changes in steady-state levels, or by changes in protein binding, etc. Measuring levels and calculating pharmacokinetic parameters is relatively straightforward. Assessing a pharmacodynamic interaction between two drugs requires a valid quantitative measurement of a specific drug effect for the two drugs individually, as well as a quantitative measurement of the effect of the two drugs administered together. Finally, it is necessary to determine the nature of the pharmacodynamic interaction that has occurred between the two drugs. Also, before the two drugs are administered together, one has to determine for each of the two drugs the appropriate dose to be administered for an assessment of the pharmacodynamic interaction to be possible. Once the response to the two drugs given together has been measured, the interaction has to be analyzed and categorized according to its type. As discussed and defined in Chapter 9 (see Table 9.1), there are four possible types of pharmacodynamic interactions: additive, supra-additive (potentiation), infra-additive (antagonism), and indifferent. Methods have been developed that make it possible to determine the type of interaction in experimental animal models. None of these methods can be applied directly to clinical studies.