CYP2D6 Drug–Drug–Gene Interaction Network Development

This article presents a technical report detailing the development of a comprehensive physiologically-based pharmacokinetic (PBPK) modeling network for cytochrome P450 (CYP) 2D6 drug-drug-gene interactions (DDGIs). The study addresses the challenges of conducting clinical studies on DDGIs and aims to inform clinical guidelines and patient-specific dosing. The network encompasses various CYP2D6 substrates and inhibitors, integrating data from 30 drug-gene interaction studies, 45 drug-drug interaction studies, and seven DDGI studies, covering 32 unique drug combinations. The predictive performance of the network is evaluated, demonstrating good accuracy for various interaction types. Additionally, the report discusses the implications of this network for clinical practice, particularly in making informed dosing decisions for patients with varying CYP2D6 enzyme activity. The findings highlight the potential of PBPK modeling to enhance the understanding of complex drug interactions and support regulatory submissions.