Background:  ART agents when used together as part of a potent regimen for the treatment of HIV infection, or in combination with other therapies can result in a number of sometimes unpredicted, drug-drug interactions. These interactions may influence treatment outcomes. As a result, a thorough evaluation of important drug-drug interactions prior to approval is critical for the safe and effective use of ART; however, it is not possible to evaluate all potential drug-drug interactions. Evaluating mechanisms of drug absorption, distribution, metabolism, and elimination early in development can help prioritize clinically important interaction studies and identify drug interaction studies essential to the overall drug development process. The goal of this presentation is to discuss the timing of drug-interaction evaluations during development and issues that affect the design of in vivo drug interaction studies, such as selection of study populations and appropriate controls. Furthermore, options for evaluating 3- or 4-way drug interactions and the role of in vivo drug interaction cocktail studies for prioritizing drug interaction studies during drug development is discussed. In addition a summary of lessons learned from drug interactions not predicted prior to conduct of an in vivo study is discussed.

Conclusions:  Drug interaction information is important for the safe use of combination ART. Early identification of potential interactions and appropriate clinical management of these interactions can lead to more effective long-term therapy by reducing drug toxicity or by delaying the development of resistance in antiretroviral naïve and experienced patients.