High-throughput PBK modelling for dermal exposure: a pragmatic approach to predict systemic pharmacokinetics

Area of Science:

• Pharmacokinetics and toxicokinetics
• Computational toxicology
• Dermal absorption and safety assessment

Background:

• High-throughput physiologically based kinetic (HT-PBK) modeling offers a mechanistic approach for predicting chemical pharmacokinetics (PK).
• It supports non-animal chemical safety assessment within next-generation risk assessment (NGRA) frameworks.
• Dermal exposure is a critical route for human contact with chemicals, necessitating robust assessment methods.

Purpose of the Study:

• To apply HT-PBK modeling to dermal exposure scenarios.
• To simulate systemic PK profiles using only in silico data (physicochemical properties from QSAR models).
• To evaluate the feasibility and accuracy of fully in silico, non-animal HT-PBK modeling for dermal absorption.

Main Methods:

• Utilized the Open Systems Pharmacology Suite's skin permeation model for simulations.
• Predicted physicochemical properties (lipophilicity, solubility) using various quantitative structure-activity relationship (QSAR) tools.
• Compared different QSAR tools to optimize HT-PBK model parameterization.
• Simulated PK profiles for 52 compounds based solely on predicted properties, without in vitro data.

Main Results:

• The best HT-PBK strategy accurately predicted Cmax (73%) and AUC (75%) within a tenfold range of observed human plasma data.
• A tendency towards overprediction of systemic PK was noted, potentially due to missing metadata and default skin hydration assumptions.
• Prediction errors for dermal exposure were larger than for oral exposure, reflecting dermal absorption complexity.

Conclusions:

• Fully in silico, non-animal HT-PBK modeling is feasible for dermal absorption assessment.
• This approach can serve as a pragmatic tool for exposure-driven safety assessment in NGRA.
• The study highlights the potential to reduce reliance on animal testing for chemical safety evaluations.