Introduction to Single-cell Physiologically-Based Pharmacokinetic (scPBPK) Models.

Area of Science:

• Pharmacokinetics and Drug Metabolism
• Computational Biology
• Systems Pharmacology

Background:

• Standard physiologically-based pharmacokinetic (sPBPK) models lack cellular resolution.
• Understanding drug disposition at the single-cell level is crucial for predicting drug response and toxicity.
• Expression-dependent (ED) processes, like metabolism and transport, introduce cell-to-cell variability.

Purpose of the Study:

• To introduce and validate single-cell physiologically-based pharmacokinetic (scPBPK) models.
• To investigate drug disposition heterogeneity at the cellular scale.
• To demonstrate the utility of scPBPK models using real-world drug examples.

Main Methods:

• Development of scPBPK models incorporating expression-dependent (ED) processes using weighting functions.
• Application of negative binomial distribution for weighting functions, common in single-cell RNA sequencing (scRNAseq) analysis.
• Simulation of drug concentrations for AZD1775 (3 ED blood-brain barrier transport) and midazolam (1 ED hepatic metabolism).

Main Results:

• scPBPK simulations revealed substantial single-cell drug concentration heterogeneity for AZD1775.
• Midazolam simulations showed less heterogeneity due to dominant membrane transport over metabolism.
• The negative binomial distribution effectively modeled ED processes and cell-specific kinetics.

Conclusions:

• scPBPK models provide a powerful framework for analyzing cellular pharmacokinetics.
• These models are compatible with high-throughput omic data, enabling deeper biological insights.
• scPBPK models can be extended to incorporate pharmacodynamic aspects for comprehensive drug effect prediction.