Clinically relevant drug-drug and drug-food interactions: Underlying mechanisms and regulatory requirements for drug licensing

Drug interactions arise when the effects of a drug are altered by the co-administration of another drug or food substance. Many factors determine the clinical response seen, including specific drug characteristics, patient age, gender and co-morbidities. The absorption, distribution, metabolism and excretion of a drug all impact upon drug availability at its sites of action and alterations in these processes can result in adverse outcomes. Similarly, the effect of a drug may be altered if co-prescribed with another drug or food substance that acts on the same receptor or physiological system. In recent years, there is a greater understanding of the mechanisms underlying pharmacokinetic and pharmacodynamic drug interactions, including phase I metabolic reactions (involving the family of cytochrome P450 isoenzymes) and the important role played by drug transporter proteins including P-glycoprotein (expressed in many tissues) and organic anion transporters. There is also a growing awareness of the impact that pharmacogenomics has on drug interaction potential, resulting in interindividual variations in drug transport, metabolism and elimination. The number of potential drug interactions is extensive, but the lower incidence seen in clinical practice implies that many of these potential interactions are not clinically relevant. However, with an ageing population, an increasing number of new drugs, more polypharmacy and the growing use of herbal remedies and over-the-counter preparations, the potential for drug interactions is rising and increasing efforts are needed to avoid them. A good knowledge of the mechanisms underlying drug interactions and the promotion of rational and safe prescribing amongst prescribers are essential in predicting (and therefore preventing) drug interactions in clinical practice. A comprehensive evaluation of drug interaction potential is now an integral part of risk assessment during early drug development, and regulatory bodies including the US FDA and the European Medicines Agency have published guidance documents that outline the importance of in vitro and (where appropriate) in vivo studies to predict interactions during drug development. This article discusses the main mechanisms involved in clinically relevant drug-drug and drug-food interactions and outlines some of the studies used to predict them during drug development. Safe prescribing is discussed along with the central role played by regulatory bodies in supporting drug development and postmarketing pharmacovigilance. © 2013 Springer International Publishing Switzerland.