**5. Conclusions**

Polypharmacy in many cases is deemed to be required and elderly patients are particularly prone to this phenomenon. Aging is associated with the presence of multiple independent chronic diseases and is almost always accompanied by multiple drug regimens. Polypharmacy has been associated with many adverse clinical outcomes, such as drug–drug interactions, leading to adverse drug events. Among these, mechanism-based inhibitor–victim drug combinations like clopidogrel and omeprazole are commonly prescribed. Drugs for overactive bladder like mirabegron and tricyclic antidepressants like paroxetine are also commonly prescribed in elderly populations. Polypharmacy is not necessarily synonymous with inappropriate treatment, but in several situations, it can lead to significant drug–drug interactions especially in the presence of mechanism-based inhibitor drugs, as described in the current review. In these cases, polypharmacy might cause problems like blunted efficacy of clopidogrel due to the co-administration of omeprazole, or increased toxicity of other drugs co-administered with paroxetine or mirabegron. Clinicians must be able to recognize and intervene appropriately based on the mechanism of these interactions.

As highlighted in this current review, mechanism-based inhibition can cause severe clinical interactions. The magnitude of these interactions and their impacts depend on the duration of the mechanism-based inhibitor exposure and the exact time-point when the victim drug is introduced into the drug regimen. Without a comprehensive understanding of this mechanism, healthcare professionals might find it di fficult to diagnose and mitigate these interactions. Separating the time of administration of interacting drugs cannot mitigate an interaction caused by mechanism-based inhibition. A careful titration of dose, monitoring of clinical e ffects, or switching to an alternate drug with a di fferent metabolic pathway may become necessary to avoid such interactions. Advanced clinical decision support systems that consider and distinguish competitive versus mechanism-based inhibition drug–drug interactions would help identify potential interactions mediated by enzyme inhibition. Using such tools can help pharmacists quickly identify and mitigate drug interactions, thus helping reduce preventable drug interactions.

**Author Contributions:** Conceptualization, M.D. and V.M.; methodology, M.D., J.T., and V.M.; resources, M.D., P.D., J.T., and V.M.; writing—original draft preparation, M.D., S.B.A.R., M.J.A., L.D., P.D., J.T., and V.M.; writing—review and editing, M.D., P.D., J.T., and V.M.; visualization, M.D.; supervision, J.T. and V.M.; project administration, P.D., J.T., and V.M. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research received no external funding.

**Acknowledgments:** The authors recognize the contribution of Ernesto Lucio for his design of the included figures. The authors would like to thank Dana Filippoli for her comprehensive review and comments pertaining to the contents of this manuscript.

**Conflicts of Interest:** Malavika Deodhar, Sweilem Al Rihani, Meghan Arwood, Lucy Darakjian, Pamela Dow, Jacques Turgeon, and Veronique Michaud are all employees and shareholders of Tabula Rasa HealthCare. The company, TRHC, had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.
