SYSTEMATIC SCREENING FOR PHARMACOKINETIC INTERACTIONS DURING DRUG DEVELOPMENT

The possible involvement of a new chemical entity in pharmacokinetic d rug interactions is an important safety issue. Not all relevant drug c ombinations for evaluation of the interactive potential of a new drug can be examined. Therefore, experiments should be selected to provide information which is valid not only for the interaction investigated, but which can be extrapolated to other comedications. In this respect the typical approaches currently used, including interaction studies w ith high risk drugs and compounds frequently given as comedication, or studies involving standard inhibitors and standard substrates are uns atisfactory. A better approach is to characterize drugs according to t heir effects on the underlying pharmacokinetic processes. Indeed, rece nt progress in understanding drug interaction mechanisms and in the de velopment and refinement of in vitro test systems enables in many case s experiments to be designed which predict the occurrence of drug inte ractions. This paper illustrates systematic investigational procedures based on mechanism of interaction. Interaction mechanisms involving d rug absorption, distribution, metabolism, and/or excretion are briefly summarized. Detailed proposals are derived which allow identification of the possible role of a new drug in interaction mechanisms for whic h valid test systems are available. Emphasis is placed on the rational selection of experiments with optimal cost-effectiveness. In vitro me thods are integrated in the schemes wherever possible. In addition, it is proposed that pharmacoepidemiological screening, starting in phase II of drug development, be used to identify those relevant drug inter actions missed by the mechanism-based approach. As exemplified by seve ral recently discovered interactions it should be possible, by impleme ntation of the proposed procedure, to avoid most serious unexpected ad verse effects due to pharmacokinetic drug interactions.