Regulatory aspects of population pharmacokinetic drug interaction studies
Medical Product Agency, Uppsala, SwedenInformation on drug-drug interactions is generally gathered form conventional Phase I studies in healthy volunteers, but information is also generated from Phase II/III using population pharmacokinetic methods. According to the European guideline for drug interactions the outcome of the latter studies should mainly be used as hypothesis generating and the best use of this approach are probably to identify unsuspected interactions as a screening instrument. Another application is to confirm absence of suspected interactions, perhaps arising from indications in vitro, which then could be reflected in the labelling. It is less likely that the approach is used to prove the absence of interactions that has been detected in in vivo conventional interaction studies. The population approach has not been used as much as the conventional studies to quantify interactions and provide dose recommendations for certain drug combinations. However, since data are obtained in the target population for whom the drug is intended, the relevance of the results is increased. Usually, the primary aim of the clinical trial is not detection of interactions and thus the design might not be optimal from a drug-drug interaction perspective. For a successful use of the population approach it is necessary that there are sufficient number of patients receiving the interacting drug and that the interacting drug is administered within a reasonable time frame in relation to the development drug. Thus, for infrequently administered drugs the population approach are of less value. In some situations it is necessary to group the interacting drugs, unless the data set contains sufficient information about a certain drug combination, and grouping by mechanism of interaction is one possible approach. Generally, the population approach has been used to evaluate the effect of other drugs on the development drug. The types of interaction mechanism studied are mainly interactions with respect to metabolism or in rare cases active transporters e.g. renal transport. Some examples will be given. Provided that care is taken to assure quality in the design, study management and data analysis, population pharmacokinetic studies to evaluate drug-drug interactions can be of great value.