@article {Yudmd.118.084905, author = {Jingjing Yu and Ichiko D. Petrie and Rene H. Levy and Isabelle Ragueneau-Majlessi}, title = {Mechanisms and Clinical Significance of Pharmacokinetic-based Drug-drug Interactions with Drugs Approved by the U.S. Food and Drug Administration in 2017}, elocation-id = {dmd.118.084905}, year = {2018}, doi = {10.1124/dmd.118.084905}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {Pharmacokinetic-based drug-drug interaction (DDI) data for drugs approved by the U.S. Food and Drug Administration in 2017 (N = 34) were analyzed using the University of Washington Drug Interaction Database. The mechanisms and clinical relevance of these interactions were characterized based on information from new drug application reviews. CYP3A inhibition and induction explained a majority of the observed drug interactions (new drugs as victims or as perpetrators), and transporters mediated about half of all DDIs, alone or with enzymes. OATP1B1/1B3 played a significant role, mediating more than half of the drug interactions with AUC changes >= 5-fold. As victims, five new drugs were identified as sensitive substrates, namely abemeciclib, midostaurin, and neratinib for CYP3A, and glecaprevir and voxilaprevir for OATP1B1/1B3. As perpetrators, three drugs were considered strong inhibitors: ribociclib for CYP3A, glecaprevir/pibrentasvir for OATP1B1/1B3, and sofosbuvir/velpatasvir/voxilaprevir for OATP1B1/1B3 and BCRP. No strong inducer of enzymes or transporters was identified. DDIs with AUC changes >= 5-fold and almost all DDIs with AUC changes 2- to 5-fold had dose recommendations in their respective drug labels. A small fraction of DDIs with exposure changes \< 2-fold had a labeling impact, mostly related to drugs with narrow therapeutic indices. As with drugs approved in recent years, all drugs found to be sensitive substrates or strong inhibitors of enzymes or transporters were among oncology or antiviral treatments, suggesting a serious risk of DDIs in these patient populations for whom therapeutic management is already complex due to poly-therapy.}, issn = {0090-9556}, URL = {https://dmd.aspetjournals.org/content/early/2018/11/15/dmd.118.084905}, eprint = {https://dmd.aspetjournals.org/content/early/2018/11/15/dmd.118.084905.full.pdf}, journal = {Drug Metabolism and Disposition} }