Do Inhibitory Metabolites Impact DDI Risk Assessment? Analysis of in vitro and in vivo Data from NDA Reviews Between 2013 and 2018

• Published in: Clinical pharmacology and therapeutics 2021-08, Vol.110 (2), p.452-463
• Main Authors: Steinbronn, Claire, Yang, Xinning, Yu, Jingjing, Dimova, Hristina, Huang, Shiew‐Mei, Ragueneau‐Majlessi, Isabelle, Isoherranen, Nina
• Format: Article
• Language: English
• Subjects: Area Under Curve; Biotransformation; Cytochrome P-450 Enzyme Inhibitors - pharmacology; Databases, Factual; Drug Interactions; Humans; Liver - metabolism; Pharmaceutical Preparations - metabolism; Pharmacokinetics; Risk Assessment
• ISSN: 0009-9236; 1532-6535
• DOI: 10.1002/cpt.2259

Evaluating the potential of new drugs and their metabolites to cause drug‐drug interactions (DDIs) is critical for understanding drug safety and efficacy. Although multiple analyses of proprietary metabolite testing data have been published, no systematic analyses of metabolite data collected according to current testing criteria have been conducted. To address this knowledge gap, 120 new molecular entities approved between 2013 and 2018 were reviewed. Comprehensive data on metabolite‐to‐parent area under the curve ratios (AUCM/AUCP), inhibitory potency of parent and metabolites, and clinical DDIs were collected. Sixty‐four percent of the metabolites quantified in vivo had AUCM/AUCP ≥ 0.25 and 75% of these metabolites were tested for cytochrome P450 (CYP) inhibition in vitro, resulting in 15 metabolites with potential DDI risk identification. Although 50% of the metabolites with AUCM/AUCP