Applications of minimal physiologically-based pharmacokinetic models

Area of Science:

• Pharmacokinetics
• Physiologically-Based Modeling
• Drug Disposition Analysis

Background:

• Conventional mammillary models for pharmacokinetic (PK) analysis rely on blood/plasma data and lack clear biological relevance.
• These models are sensitive to data quality and offer limited biological interpretability.

Purpose of the Study:

• To propose and validate a minimal-physiologically-based pharmacokinetic (minimal-PBPK) modeling approach.
• To demonstrate the utility of minimal-PBPK models in analyzing drug disposition data with enhanced physiological relevance and interpretability.

Main Methods:

• Developed minimal-PBPK models by integrating core physiological attributes like blood/tissue volumes, cardiac output fractions, tissue/blood partitioning (K(p)), and clearance.
• Applied minimal-PBPK models to diverse therapeutic agents, including beta-lactam antibiotics, hepatic elimination drugs, moxifloxacin across species, and monoclonal antibodies.

Main Results:

• Minimal-PBPK models accurately captured human PK profiles for 22 beta-lactam antibiotics, enabling comparison of K(p) values.
• Integration with a hepatic compartment allowed joint fitting of oral/IV data for hepatic drugs, yielding distinct clearance and bioavailability estimates.
• Allometric scaling with minimal-PBPK successfully described moxifloxacin PK in five species.
• Tissue-based clearance models effectively characterized monoclonal antibody plasma concentrations in humans.

Conclusions:

• The minimal-PBPK modeling approach provides a physiologically rational and interpretable alternative to traditional compartmental models for PK analysis.
• This method enhances the understanding of drug disposition by incorporating key physiological parameters.