FDA evaluations using in vitro metabolism to predict and interpret in vivometabolic drug-drug interactions: Impact on labeling

Recent advances in in vitro metabolism methods have led to an improved abil ity to predict clinically relevant metabolic drug-drug interactions. To add ress the relationships of in vitro metabolism data and in vivo metabolism o utcomes, the Office of Clinical Pharmacology and Biopharmaceutics in the Ce nter for Drug Evaluation and Research, Food and Drug Administration, evalua ted a number of recently approved new drug applications. The goal of these evaluations was to determine the contribution of in vitro metabolism data i n (1) predicting in vivo drug-drug interactions, (2) determining the need t o conduct on in vivo drug-drug interaction study, and (3) incorporating fin dings into drug product labeling. Ten cases are presented in this article. They fall into two major groups: (1) in vitro data were predictive of in vi vo results, and (2) in vitro data were not predictive of in vivo results. D iscussion of these cases highlights factors limiting predictability of in v ivo metabolic interactions fi om in vitro metabolism data. The integration of these findings into drug product labeling is also discussed. Journal of Clinical Pharmacology 1999;39:899-910 (C) 1999 the American College of Clin ical Pharmacology.