(T0930-08-53) Modeling Metamorphosis: Advancing Dermal PBPK Modeling – A Metronidazole Case Study

Purpose: Formulation metamorphosis refers to the series of physical and compositional changes that a topical formulation undergoes after application to the skin, including (but not limited to) processes such as solvent evaporation, change in inactive ingredient composition, and the potential formation of a residual film following precipitation depending on the solubility of the API in the remaining phase. These changes dynamically alter the formulation’s microstructure and the thermodynamic activity of the drug, directly impacting local bioavailability. Therefore, accurately capturing formulation metamorphosis within Physiologically Based Pharmacokinetic (PBPK) models is essential for understanding and predicting skin absorption and supporting reliable bioequivalence assessments for topical drug products. Using metronidazole (MTZ) as a model compound and a series of binary and tertiary aqueous and gel formulations, this work leverages PBPK modeling to study how formulation attributes and metamorphosis affect skin bioavailability for topical products.

Methods: The Transdermal Compartmental Absorption & Transit (TCAT™) model [1] in GastroPlus® v9.9 was used to simulate MTZ in vitro permeation testing (IVPT) studies performed with Franz diffusion cells for MTZ (cc. 21.07 mg/mL) polyethylene glycol 200 (PEG200): hydroxyethyl cellulose (HEC) gels and a MTZ (cc. 5.0 mg/mL) water: propylene glycol (PG) 50:50 solution. The PEG200-HEC gel data used different excipient composition. MTZ physicochemical properties were extracted from the literature, and skin permeation parameters for the stratum corneum (SC) and viable skin (epidermis and dermis) were estimated using the semi-empirical Potts-Guy and Bunge-Cleek equations within the TCAT model, respectively. It should be noted that the Potts-Guy equation is specific to aqueous vehicles; as a starting point, in this simulation, potential effects of the non-aqueous vehicle (PG) were not explicitly accounted for. Formulation specific parameters (dosage form: solution, gel, volume applied, MTZ solubility in the vehicle, and evaporation rate of volatile components) were experimentally determined for each formulation. Under finite dosing conditions, MTZ precipitation was modeled as occurring immediately (1 second) to prevent supersaturation during solvent loss. Simulations were compared with the available data in the literature. For MTZ solutions, simulations were compared with observed MTZ amounts in the stratum corneum (SC), viable skin layers, and receptor solution. For gels, predictions were compared to the available MTZ flux profiles under both finite and infinite dosing conditions.

Results: Initial simulations with PG: water solutions underestimated MTZ in the SC and viable skin, but predictions for the receptor compartment were within data variability. Increasing the SC partition coefficient (Ksc) improved predictions in the SC but tended to overestimate MTZ in the receptor compartment (Fig 1). This suggests PG may influence MTZ partitioning into and diffusivity within the SC. However, uncertainty remains due to potential limitations of the Potts-Guy model, and additional IVPT data in water without PG are needed to clarify these effects. Simulations of PEG200:HEC gels with varying PEG200 (1%, 10%, or 20%) yielded predictions within 1.5-fold of the observed values at steady state flux predictions under infinite dosing (Figure 2A). However, for finite dosing, initial models consistently overestimated flux beyond 6 hours for all gels, regardless of PEG200 content (Figure 2B-D). For these gels, evaporation rates and residual volumes included in the model were determined by gravimetric testing, and the application time in the initial simulations matched the experimental duration (24 hours), assuming a minimal formulation volume (1%) remaining on the skin surface after evaporation. Adjusting the product application time resulted in an accurate prediction of the observed flux across all gels (Fig. 2, dotted lines). These results suggest that formulation metamorphosis leading to immediate MTZ precipitation prevents further MTZ skin uptake from the residual formulation on the skin surface.

Conclusion: This work demonstrates the utility of PBPK modeling in understanding and predicting the interplay between formulation properties, metamorphosis, and skin permeation. For the PG: water solutions, the model successfully predicted total MTZ delivery to the receptor solution and highlighted the importance of accounting for the role of PG as both a solubility modifier in the formulation and in the skin. However, the results suggest that PG may primarily influence MTZ partitioning into and diffusivity within the SC. This can be addressed by dynamically increasing the partition coefficient (K) and/or diffusivity of the API in the SC as PG permeates into the skin with the API. This inclusion will be incorporated in upcoming simulation work.Simulations with the TCAT model accurately reproduced MTZ flux under infinite dosing and provided mechanistic insight into the MTZ permeation under finite dosing with PEG200:HEC gels, indicating that solvent evaporation and MTZ precipitation may prevent further MTZ delivery into the skin when a critical formulation volume is reached on the skin surface.

References: 1. van Osdol, W.W.N., J.; Le Merdy, M.; Tsakalozou, E.; Ghosh, P.; Spires, J.; Lukacova, V., Predicting Human Dermal Drug Concentrations Using PBPK Modeling and Simulation: Clobetasol Propionate Case Study. AAPS PharmSciTech, 2024. 25(3): p. 39.

Acknowledgements: This project was supported by the Food and Drug Administration (FDA) of the U.S. Department of Health and Human Services (HHS) as part of a financial assistance award [FAIN] U01FD007957 with 100 percent funded by FDA/HHS. The contents are those of the author(s) and do not necessarily represent the official views of, nor an endorsement, by FDA/HHS, or the U.S. Government. This abstract/poster reflects the views of the author and should not be construed to represent FDA’s views or policies.

Figure 1. Simulations were compared with an IVPT study involving a 4-hour application of MTZ in a PG/water solution, performed using a standard Franz cell setup after application of the solution without occlusion (dose: 110µL/1.77cm2). Left: Measured () vs. Simulated (solids lines) at 1xKsc (Ksc predicted by the Potts-Guy equations-blue), 1.5xKsc (green) and 2xKsc (red) MTZ concentrations at different SC depths. Right: Measured (dark blue) vs. Simulated % of the applied dose delivered into the skin and into the different skin compartments at 1xKsc (blue), 1.5xKsc (green) and 2xKsc (red).

Figure 2. Simulations compared with IVPT study of 24 h applications of MTZ in PEG200:HEC in a stadard Franz-cell setup. A: Measured (□) vs. simulated (dashed) MTZ flux profiles from PEG200:HEC gels at different doses under infinite dosing (dose: 2mL/cm2). B, C, D: Measured (□) MTZ flux from 0.5% MTZ HEC gels with (B) 1%, (C) 10%, (D) 20% PEG200 under finite dosing (300µL/cm2) vs. simulated profiles at (dashed) 24-h, (dash-dotted) 6-h, and (dotted) 2-h application times.