Risk of Clinically Relevant Pharmacokinetic-Based Drug-Drug Interactions with Drugs Approved by the U.S. Food and Drug Administration Between 2013 and 2016

• Published in: Drug metabolism and disposition Vol. 46; no. 6; pp. 835 - 845
• Main Authors: Yu, Jingjing, Zhou, Zhu, Tay-Sontheimer, Jessica, Levy, René H., Ragueneau-Majlessi, Isabelle
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.06.2018; American Society for Pharmacology and Experimental Therapeutics, Inc
• Subjects: Antiviral agents; ATP Binding Cassette Transporter, Subfamily B, Member 1 - metabolism; CYP1A2 protein; CYP2D6 protein; Cytochrome P-450 Enzyme Inducers - pharmacokinetics; Cytochrome P-450 Enzyme System - metabolism; Cytochrome P450; Drug interaction; Drug interactions; Drug Interactions - physiology; Drugs; FDA approval; Food; Glycoproteins; Humans; Membrane Transport Proteins - metabolism; Oncology; P-Glycoprotein; Pharmaceutical Preparations - metabolism; Pharmacokinetics; Pharmacology; Substrates; United States; United States Food and Drug Administration; United States > US; BCRP; PGx; OCT; FDA; OAT; P-gp; FDC; NME; DDI; PBPK; CNS; MRP; NDA; OATP; NTR; AUC; UM; P450; PK; DME
• DOI: 10.1124/dmd.117.078691
• ISSN: 0090-9556; 1521-009X

A total of 103 drugs (including 14 combination drugs) were approved by the U.S. Food and Drug Administration from 2013 to 2016. Pharmacokinetic-based drug interaction profiles were analyzed using the University of Washington Drug Interaction Database, and the clinical relevance of these observations was characterized based on information from new drug application reviews. CYP3A was involved in approximately two-thirds of all drug-drug interactions (DDIs). Transporters (alone or with enzymes) participated in about half of all interactions, but most of these were weak-to-moderate interactions. When considered as victims, eight new molecular entities (NMEs; cobimetinib, ibrutinib, isavuconazole, ivabradine, naloxegol, paritaprevir, simeprevir, and venetoclax) were identified as sensitive substrates of CYP3A, two NMEs (pirfenidone and tasimelteon) were sensitive substrates of CYP1A2, one NME (dasabuvir) was a sensitive substrate of CYP2C8, one NME (eliglustat) was a sensitive substrate of CYP2D6, and one NME (grazoprevir) was a sensitive substrate of OATP1B1/3 (with changes in exposure greater than 5-fold when coadministered with a strong inhibitor). Approximately 75% of identified CYP3A substrates were also substrates of P-glycoprotein. As perpetrators, most clinical DDIs involved weak-to-moderate inhibition or induction. Only idelalisib showed strong inhibition of CYP3A, and lumacaftor behaved as a strong CYP3A inducer. Among drugs with large changes in exposure (≥5-fold), whether as victim or perpetrator, the most-represented therapeutic classes were antivirals and oncology drugs, suggesting a significant risk of clinical DDIs in these patient populations.