Evaluation of a generic physiologically based pharmacokinetic model for lineshape analysis

Area of Science:

• Pharmacokinetics
• Computational modeling
• Drug development

Background:

• Physiologically based pharmacokinetic (PBPK) models offer a mechanistic framework for hypothesis testing and analyzing concentration-time profiles.
• PBPK models are valuable for understanding the mechanisms driving observed pharmacokinetic behaviors.

Purpose of the Study:

• To evaluate the utility of PBPK models for simulating oral drug "lineshapes" (concentration-time profiles).
• To optimize clearance and distribution parameters by fitting observed intravenous pharmacokinetic profiles for subsequent oral simulations.

Main Methods:

• A generic PBPK model was developed in MATLAB, incorporating absorption, metabolism, distribution, and elimination pathways.
• The model utilized physicochemical properties (log P, pKa, solubility) and in vitro data (Caco-2 permeability, unbound fraction, intrinsic clearance) for nine diverse drugs.
• Intravenous profiles were simulated to optimize clearance and distribution parameters, which were then used to predict oral profiles.

Main Results:

• The PBPK modeling approach successfully predicted oral concentration-time profiles for the nine studied drugs.
• The mean fold error for key pharmacokinetic parameters (Cmax, Tmax, AUC) and lineshape simulation was within 2-fold.

Conclusions:

• PBPK simulations using optimized parameters from intravenous data provide good agreement with observed oral profiles when absorption is solubility and permeability-limited.
• Discrepancies between simulated and observed oral profiles can yield mechanistic insights into pharmacokinetic processes.
• A strategy was proposed to identify specific pharmacokinetic mechanisms like carrier-mediated transport and enterohepatic recirculation.