Tutorial Drug–Drug Interactions

A recent article offers a useful summary of steps to consider concerning drug–drug interactions during drug development [1]. However, the article focused mainly on anticipating pharmacokinetic and drug metabolism-based interactions. The more important issue is that while in some cases such changes can anticipate potentially clinically important interactions, for example, with drugs acting directly on peripheral cardiovascular receptors or having a small volume of distribution, for many classes of drugs such studies cannot usefully predict clinically important interactions in individual patients [2, 3]. The reasons are mainly because of the large variation among patients in the extent of kinetic and metabolism changes combined with much larger variation in pharmacodynamic and therapeutic effects. Preoccupation with kinetic and metabolic-based interactions mechanisms has occurred because these are more easily studied than the more important pharmacodynamic consequences in individual patients. Population (average) changes in kinetics, metabolites and pharmacodynamics are not useful in actual clinical dose adjustment. This shortcoming is compounded by the relative lack of clinical studies in actual conditions and settings of drug use and in neglected study populations including different ancestry groups, low socioeconomic groups and individuals with restricted access to health care services. As a result of being understudied, much clinical use of drugs and management of drug–drug interactions is largely trial and error. Many more “real” world post-marketing studies of drug–drug interactions are needed. As final comment, these authors elect to distinguish the drugs involved in drug–drug interactions as the “perpetrator” and the “victim.” This is a useful categorical and semantic shortcut but belies the complexity of the etiology and complexity of drug–drug interactions where often multiple drugs are administered concurrently in disease states that modify mechanism and consequences. In clinical practice, the perpetrator is often the prescriber and the victim the patient! The author has nothing to report. The author declares no conflicts of interest.