Pharmacokinetics in organs and the intact body: model validation and reduction

Area of Science:

• Pharmacokinetics and Drug Metabolism
• Physiological Modeling
• Systems Biology

Background:

• Physiological pharmacokinetic models traditionally simplify organ-level drug distribution, often neglecting intravascular dispersion and tissue diffusion.
• Existing models typically treat organs as well-stirred compartments, limiting their accuracy in reflecting complex biological transport processes.

Purpose of the Study:

• To introduce and discuss advanced recirculatory pharmacokinetic models based on residence time theory.
• To address the limitations of conventional models by incorporating a more realistic representation of circulatory transport.
• To present methods for obtaining quantitative subsystem information in vivo, overcoming global model unidentifiability from plasma data.

Main Methods:

• Utilizing residence time theory to decompose the body into natural subsystems for modeling.
• Discussing experimental designs for in vivo quantitative data acquisition: (i) destructive sampling for tissue concentration-time profiles, (ii) input/output profiling for organ transit time density estimation.
• Applying a reduced-complexity recirculatory model to clinical pharmacokinetic data.

Main Results:

• Recirculatory models provide a more general framework for body decomposition into subsystems.
• Specific experimental designs enable the acquisition of quantitative data for individual organs or subsystems.
• Demonstrated feasibility of applying these models to clinical data for improved pharmacokinetic understanding.

Conclusions:

• Recirculatory pharmacokinetic models offer a superior approach to understanding drug distribution compared to traditional compartmental models.
• The discussed methods facilitate in vivo quantitative assessment of organ-specific drug kinetics.
• These advanced modeling strategies hold significant potential for refining drug development and clinical application.