Phys-DAT: A physiologically-based pharmacokinetic model for unraveling the dissolution, transit and absorption...

Area of Science:

• Pharmacokinetics and Drug Metabolism
• Computational Biology and Bioinformatics
• Pharmaceutical Sciences

Background:

• Physiologically-based pharmacokinetic (PBPK) software requires greater flexibility for complex LADME processes.
• In silico methods are crucial for efficient drug property testing and qualification.
• Oral drug absorption modeling demands advanced computational tools.

Purpose of the Study:

• To develop a mechanistic modeling framework (Phys-DAT) for dissolution, transit, and absorption processes.
• To integrate Phys-DAT into the PhysPK platform.
• To assess the predictive power of the acausal MOOM methodology within Phys-DAT against ODE-based PBPK software.

Main Methods:

• Developed a PBPK model incorporating thermodynamic states of the drug (unreleased, undissolved, dissolved).
• Represented the GI tract with nine compartments and first-order transit kinetics.
• Modeled dissolution using solubility-dependent/independent mechanisms and pH effects; employed linear transit and absorption mechanisms for passive diffusion.
• Validated the Phys-DAT model internally (simulation-based) and externally (in silico/in vivo data) for BCS I and II drugs.

Main Results:

• The Phys-DAT model accurately predicts plasma concentration profiles, Cmax, Tmax, and AUC0-t for BCS I and II drugs.
• Internal and external validations confirmed alignment with theoretical assumptions and good predictive performance.
• Calculations of AFE, AAFE, and PPE indicated that predicted/observed ratios were within acceptable ranges.

Conclusions:

• Phys-DAT provides a mechanistic approach to predict oral absorption, encompassing dissolution, pH effects, transit, and absorption.
• The PhysPK platform demonstrates strong prediction accuracy, comparable to ODE-based PBPK software.
• The Phys-DAT model shows reliable predictions for orally administered drugs in healthy volunteers, supporting the interchangeability of acausal MOOM methodology.