Ongoing Challenges in Drug Interaction Safety: from Exposure to Pharmacogenomics

Summary:The complex transporter-cytochrome P450 (CYP) enzyme interplay in the disposition of drugs makes it very challenging to address the safety of clinical drug interactions. Thus, two major subjects are discussed herein. First, the concept of an intravenous drug interaction study (where the perpetrator is administered intravenously or orally while the drug candidate administered intravenously) to facilitate prediction of maximal possible systemic exposure of a substrate drug when oral drug interactions occur is explored. If a substrate drug with oral bioavailability is equal to or less than 80%, an intravenous drug interaction study at low dose along with a few key oral drug interaction studies could be useful for achieving this objective with the aid of modeling and simulations. Along with the clinical safety of the drug, one could then attempt to predict the safety margin when the worst drug interactions occur. Secondly, the efficacy and safety disparity of clopidogrel, statins and irinotecan each among races and genetic variants are discussed to illustrate that pharmacogenetic knowledge is important for the interpretation and prediction of drug interaction-induced adverse events, whereas drug interaction -induced adverse events are equally informative for identifying genes-based mechanisms involved.