Structural and functional pharmacokinetic analogs for physiologically based pharmacokinetic (PBPK) model evaluation

Area of Science:

• Toxicology and Pharmacology
• Computational Chemistry
• Risk Assessment

Background:

• Physiologically based pharmacokinetic (PBPK) models simulate chemical behavior in the body.
• Evaluating PBPK models typically requires chemical-specific pharmacokinetic (PK) data, which is often unavailable.
• Limited PK data hinders the widespread use and acceptance of PBPK models in safety assessments.

Purpose of the Study:

• To test if PBPK models for a target chemical can be evaluated using PK data from a different, source chemical.
• To explore analog-based approaches for PBPK model evaluation in the absence of target chemical PK data.
• To support the development of animal-free safety assessment strategies by reducing the need for new PK data generation.

Main Methods:

• Two analog identification techniques were employed: structural PK analogs and functional PK analogs.
• These methods were used to select source chemicals with existing PK data.
• Oral human PBPK models were evaluated using the PK data from identified source chemical analogs.

Main Results:

• Both structural and functional analog approaches successfully identified source chemicals with similar PK profiles to the target chemical.
• The identified PK analogs provided a viable alternative for evaluating PBPK models.
• This demonstrates the feasibility of using existing PK data from analogous compounds for PBPK model assessment.

Conclusions:

• PBPK models can be effectively evaluated using PK data from structurally or functionally similar chemicals.
• Analog-based evaluation methods offer a practical solution when target chemical PK data is limited or absent.
• These findings contribute to advancing animal-free safety assessment methodologies by enabling PBPK model evaluation without new data generation.