A multi-organ MPS-PBPK workflow for profiling CYP2D6 population poster activity through Dextromethorphan metabolism

New approach methodologies (NAMs) are now delivering on their promise as practical alternatives that accelerate and improve drug discovery.

Conventional in vitro and in vivo models used to estimate absorption, clearance and oral bioavailability often lack translational reliability, resulting in poor prediction of clinical dosing for Investigational New Drug applications. While physiology based pharmacokinetic (PBPK) modeling can help bridge this gap by integrating preclinical data into a systems-level framework, its predictive performance is fundamentally limited by quality, mechanistic scaling and human relevance of the input parameters. 

This work presents a microphysiological system (MPS)-to-PBPK workflow for clinical dose prediction from MPS-derived time course data. As an example, the enzyme Cytochrome P450 2D6 (CYP2D6) was chosen as a highly polymorphic enzyme exhibiting substantial interindividual variability in metabolic activity. Consequently, drugs metabolized by CYP2D6 frequently require dose adjustment based on patient-specific activity scores. Dextromethorphan was utilized as a probe substrate for the CYP2D6 enzyme. 

In this study, a primary human Gut/Liver MPS was utilized to generate human-relevant parameters. This system utilizes primary cells using RepliGut® Planar jejunal epithelial monolayers and liver microtissue derived from human hepatocyte donors. Experimental concentration-time profiles from the MPS were used to construct an in silico compartmental model, enabling estimation of key parameters including intestinal absorption, hepatic intrinsic clearance and first-pass extraction. These experimentally derived parameters were subsequently scaled and incorporated into a PBPK model for prediction of clinical pharmacokinetics. 

Authors: Joseph Broomfield, Alexandra Morse, Morné van Wyk, Yassen Abbas, Tomasz Kostrzewski – CN Bio