A framework for 2-stage global sensitivity analysis of GastroPlus™ compartmental models

Area of Science:

• Pharmacokinetics and Drug Development
• Computational Modeling and Simulation
• Regulatory Science

Background:

• Physiologically based pharmacokinetic (PBPK) models are increasingly vital for regulatory submissions.
• Parameter sensitivity and uncertainty analysis are crucial for PBPK model validation.
• The need for robust global sensitivity analysis in PBPK modeling requires further investigation.

Purpose of the Study:

• To demonstrate the benefits of global sensitivity analysis for PBPK models.
• To implement and evaluate an automated framework for sensitivity analysis in GastroPlus™.
• To assess the alignment of sensitivity analysis results with the biopharmaceutical classification system.

Main Methods:

• Developed an integrated framework automating GastroPlus™ GUI with AutoIt and MATLAB® for sensitivity analysis.
• Employed a two-stage global sensitivity analysis: Morris method for parameter screening and Sobol's analysis for quantitative assessment.
• Applied the framework to four drugs (acetaminophen, risperidone, atenolol, furosemide) within the GastroPlus™ platform.

Main Results:

• The two-stage approach significantly reduced computational cost while maintaining interpretability of PBPK model behavior.
• Sensitivity results demonstrated good alignment with the biopharmaceutical classification system.
• Both Morris and Sobol' methods identified nonlinearities and parameter interactions missed by local sensitivity analysis.

Conclusions:

• Global sensitivity analysis provides a more comprehensive understanding of PBPK model behavior compared to local methods.
• The developed automated framework efficiently performs extensive sensitivity analysis, reducing computational burden.
• Future work will explore input domain influence and extend the framework to whole-body PBPK models.