Optimization of Bottom-Up PBPK Model Development in SIMCYP via Retrospective Analysis of Clinical Human PK Data.

ABSTRACT: Physiologically-based pharmacokinetic (PBPK) modeling has become a major tool in drug discovery and development. Here, we describe the bottom-up PBPK modeling approaches employed at AbbVie using Simcyp Simulator and evaluate the impact of three system parameters, GI physiology, P-gp Relative Expression Factor (REF), and recombinant CYP enzyme (rCYP) intersystem extrapolation factor (ISEF), independently and in combination, on PBPK prediction performance through retrospective analysis of 8 clinical assets. Overall, the application of New GI physiology resulted in a considerable improvement in the prediction of oral absorption for most compounds compared to the Original GI physiology (C_max: 76% vs. 43% within 3-fold) when using the default P-gp REF (1.5) and adjusted ISEF. Decreas

SUBMITTER: Schulz Pauly JA 

PROVIDER: S-EPMC12631063 | biostudies-literature | 2025 Nov

REPOSITORIES: biostudies-literature