A Comprehensive CYP2D6 Drug–Drug–Gene Interaction Network for Application in Precision Dosing and Drug Development

作者：Simeon Rüdesheim, Helena Leonie Hanae Loer, Denise Feick, Fatima Zahra Marok, Laura Maria Fuhr, Dominik Selzer, Donato Teutonico, Annika R. P. Schneider, Juri Solodenko, Sebastian Frechen, Maaike van der Lee, Dirk Jan A. R. Moes, Jesse J. Swen, Matthias Schwab, Thorsten Lehr · 发表于：Clinical Pharmacology & Therapeutics · 年份：2025 · DOI：10.1002/cpt.3604 · 被引用次数：11 · 研究领域：Pharmacogenetics and Drug Metabolism、Analytical Chemistry and Chromatography、Computational Drug Discovery Methods

Conducting clinical studies on drug-drug-gene interactions (DDGIs) and extrapolating the findings into clinical dose recommendations is challenging due to the high complexity of these interactions. Here, physiologically-based pharmacokinetic (PBPK) modeling networks present a new avenue for exploring such complex scenarios, potentially informing clinical guidelines and handling patient-specific DDGIs at the bedside. Moreover, they provide an established framework for drug-drug interaction (DDI) submissions to regulatory agencies. The cytochrome P450 (CYP) 2D6 enzyme is particularly prone to DDGIs due to the high prevalence of genetic variation and common use of CYP2D6 inhibiting drugs. In this study, we present a comprehensive PBPK network covering CYP2D6 drug-gene interactions (DGIs), DDIs, and DDGIs. The network covers sensitive and moderate sensitive substrates, and strong and weak inhibitors of CYP2D6 according to the United States Food and Drug Administration (FDA) guidance. For the analyzed CYP2D6 substrates and inhibitors, DD(G)Is mediated by CYP3A4 and P-glycoprotein were included. Overall, the network comprises 23 compounds and was developed based on 30 DGI, 45 DDI, and seven DDGI studies, covering 32 unique drug combinations. Good predictive performance was demonstrated for all interaction types, as reflected in mean geometric mean fold errors of 1.40, 1.38, and 1.56 for the DD(G)I area under the curve ratios as well as 1.29, 1.43, and 1.60 for DD(G)I maximum plasma...