PI-078 - LEVERAGING A DERMAL PHYSIOLOGICALLY BASED PHARMACOKINETIC MODEL OF A TOPICAL CREAM TO EXPLORE THE BIOEQUIVALENCE SAFE SPACE FOR INFLUENTIAL FORMULATION ATTRIBUTES.

Q. Duong¹, K. Alam², A. Babiskin², L. Zhao², E. Tsakalozou²; ¹US Food and Drug Administration, Columbia, MD, USA, ²US Food and Drug Administration, Silver Spring, MD, USA.

Background: Dermal physiologically based pharmacokinetic (PBPK) modeling can be used to describe skin permeation of active ingredients formulated as dermatological drug products1. The objective of this work was to develop a practice that can be used to explore the safe space (formulation space where a drug product is expected to be bioequivalent) for drug product quality attributes impacting bioavailability (BA) for a ketoconazole (KTZ) topical cream.

Methods: The Multi-Layer Multi-Phase Mechanistic Dermal Absorption, the in vitro permeation testing (IVPT) and the virtual bioequivalence (VBE) models in the Simcyp® Simulator v21 (Certara, NJ, USA) were used. The model integrated both in vitro characterization and IVPT data2 from the literature. KTZ systemic disposition in the dermal PBPK model was informed from an oral absorption full-body PBPK model previously published3. IVPT study data2 were utilized to optimize selected model parameters and establish an in vitro-in vivo extrapolation (IVIVE).

Results: The predicted KTZ flux profile described the observed data well. The in vivo dermal PBPK model predicted limited KTZ permeation to skin layers deeper than the stratum corneum. The safe space for apparent viscosity, a formulation attribute predicted to impact skin permeation per the developed model, was found to extend between 12,590 and 19,750 cps.

Conclusion: This work suggests that in the absence of direct measurements for skin biodistribution, dermal PBPK modeling, when properly verified and validated, may provide an insight on the extent of skin permeation for certain active ingredients and explore the safe space for impactful product quality attributes impacting BA to inform decisions on drug development programs and support BE assessments for dermatological products.

1. Tsakalozou E, Alam K, Babiskin A, Zhao L. Physiologically-Based Pharmacokinetic Modeling to Support Determination of Bioequivalence for Dermatological Drug Products: Scientific and Regulatory Considerations. Clin Pharmacol Ther 111 1036-1049. (2022)
2. Raney SG, Ghosh P, Ramezanli T, Lehman PA, Franz TJ. Cutaneous Pharmacokinetic Approaches to Compare Bioavailability and/or Bioequivalence for Topical Drug Products. Dermatol Clin 40 319-332. (2022)
3. Pathak SM, et al. Model-Based Analysis of Biopharmaceutic Experiments To Improve Mechanistic Oral Absorption Modeling: An Integrated in Vitro in Vivo Extrapolation Perspective Using Ketoconazole as a Model Drug. Mol Pharm 14 4305-4320. (2017)