On the development of physiologically based toxicokinetic (PBTK) models for cardiovascular implants

Area of Science:

• Biomedical Engineering
• Toxicology
• Computational Biology

Background:

• Metal ion leaching from medical devices poses health risks.
• Regulatory bodies mandate stringent quality and safety standards for medical devices.
• Modeling and simulation are recommended for medical device submissions.

Purpose of the Study:

• To enhance a physiologically based toxicokinetic (PBTK) model for predicting metal ion release from medical devices.
• To incorporate improved physiological representation and time-dependent biokinetic parameters.
• To provide a computational tool for optimizing device design and toxicological risk assessment.

Main Methods:

• Expansion of a PBTK model with an additional tissue compartment and time-dependent functions.
• Application of probabilistic, Monte Carlo methodology for confidence intervals and variability analysis.
• Validation of model predictions against human and minipig data from nickel-containing cardiovascular devices.

Main Results:

• The enhanced PBTK model accurately predicts metal ion biodistribution.
• Model validation confirmed quantitative consistency with in vivo data.
• A novel methodology for compartmental toxicological risk assessment was developed.

Conclusions:

• The enhanced PBTK model serves as a valuable computational tool for medical device development.
• The model aids in safeguarding against excessive substance release and ensuring patient safety.
• This approach supports regulatory compliance and optimizes device performance.