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The Impact of Using Measured In Vitro Data to Develop Physiologically Based Pharmacokinetic Models of Dermal
Yanling Zhang1, James F Clarke2, Yuri Dancik2
1Certara Predictive Technologies, Certara, Sheffield, UK. yanling.zhang@certara.com.
The AAPS Journal
|September 2, 2025
Summary
This study developed a dermal physiologically based pharmacokinetic (PBPK) model for caffeine to improve in vitro permeation testing (IVPT) interpretation and in vitro-to-in vivo extrapolation. The validated PBPK model aids in predicting skin concentrations and defining bioequivalence parameters for dermal drug products.
Area of Science:
- Pharmacokinetics and Drug Delivery
- Computational Modeling in Pharmacology
- Dermal Permeation Science
Background:
- In vitro permeation testing (IVPT) faces challenges with variability and statistical power for dermal drug delivery assessment.
- Dermal physiologically based pharmacokinetic (PBPK) models offer a mechanistic approach to interpret IVPT data and enable in vitro-to-in vivo extrapolation.
- Accurate modeling is crucial for understanding drug behavior in the skin and optimizing product development.
Purpose of the Study:
- To develop and validate a bottom-up dermal PBPK model for caffeine.
- To enhance the predictive reliability of PBPK models by incorporating formulation specifics and analytical method constraints.
- To utilize the PBPK model for in vitro-to-in vivo extrapolation and to explore virtual bioequivalence for dermal formulations.
Main Methods:
- A bottom-up dermal PBPK model for caffeine was constructed with minimal parameter optimization.
- The model integrated formulation properties, measured skin partition coefficients, and predicted diffusion coefficients.
- Model validation was performed against literature IVPT data, followed by simulations for ointments, emulsions, and gels with enhancers.
Main Results:
- The developed dermal PBPK model demonstrated improved predictive reliability compared to previous iterations.
- The model successfully simulated caffeine permeation from various formulations, including aqueous solutions, ointments, and emulsions.
- Predictions of in vivo skin concentrations were made for gel formulations containing propylene glycol, a penetration enhancer.
Conclusions:
- The validated dermal PBPK model provides a robust tool for interpreting IVPT data and extrapolating findings from in vitro to in vivo.
- The model supports the exploration of virtual bioequivalence and the definition of "safe spaces" for dermal product development.
- This mechanistic modeling approach offers valuable insights for regulatory submissions and optimizing dermal drug product design.
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