(M1530-05-25) Enhanced Understanding of the Relationship between Drug Product Structure and Its Performance by Using Modeling and Simulation - A Case Study with Dapsone Topical Gel

Purpose: The product specific guidances (PSG) issued by the Office of Generic Drugs at the Food and Frug Administration on dapsone topical gel for both strengths (5% and 7.5%) each recommended two options to demonstrate BE between a test product and the reference standard (RS): Option 1 is for a test product that has no difference relative to the RS in inactive ingredient components or composition, or in other aspects of the formulation (e.g., physicochemical and structural (Q3) attributes) that may significantly affect the local or systemic bioavailability (BA); it is a characterization based bioequivalence (BE) approach that involves an in vitro release test (IVRT) BE study, an in vitro permeation test (IVPT) BE study, a BE study with pharmacokinetic (PK) endpoints, and other product characterization tests. Option 2 is a comparative clinical endpoint BE study. Dapsone topical gels, 5% and 7.5% are single-phase gel products in which dapsone is partially dispersed in the formulation. The recommendations in draft PSGs for other single phase topical gel products (irrespective of the physical state of the active pharmaceutical ingredient in the formulation, completely dissolved or dispersed), reflect that the risks associated with potential failures modes for BE with a test product compared to the RS are adequately mitigated by demonstrations of no significant difference in formulation components and composition, Q3 sameness, and an equivalent drug release rate using a validated IVRT method, without direct assessments of local and systemic BA from IVPT and in vivo PK BE studies, respectively. The goal of the current work was to utilize a model-based approach to understand the structure-performance relationship of dapsone topical gels by evaluating the impact of Q3 attributes of dapsone gel (e.g., the particle size distribution and rheology) on local and systemic BA following topical application of the drug product.

Methods: Briefly, for abbreviated new drug applications (ANDAs), dermal physiologically based pharmacokinetic (PBPK) models were developed for the prospective generic (test) product and the RS by leveraging the Q3 characterization data that were generated by the applicant for these products in support of their ANDA submission. The developed models were validated using in vivo PK data from the in vivo BE studies with PK endpoints and IVPT data supporting the ANDAs. The models for the test products and the RS were then utilized to predict dapsone BA locally in the skin and in the plasma of virtual healthy subjects and assess BE in the stratum corneum (SC), dermis and the plasma between the test product and the RS. The virtual BE (VBE) assessments performed mirrored the pivotal in vivo BE studies with PK endpoints that supported the ANDA submissions. The Multi-phase, multi-layer Mechanistic Dermal Absorption model in Simcyp Simulator V22 was utilized for model building and the VBE Module within the simulator was utilized for the virtual BE (VBE) assessments.

Results: The results demonstrated that when the test product and the RS are Q3 the same, especially with respect to apparent viscosity and particle size distribution, they are found to be bioequivalent in the plasma within the scope of a VBE assessment, in accordance with the outcome of the in vivo BE study with PK endpoints. Additionally, by leveraging the capability of dermal PBPK models to predict dapsone exposure not only in the plasma (systemic circulation), but also in the different skin layers, the virtual BE assessments showed that for all ANDAs where a VBE was performed, the test product and RS were found to be bioequivalent in the stratum corneum and the dermis. The results are limited to test products that meet the criteria for no significant difference in components or composition, as specified in the aforementioned draft PSGs for dapsone topical gels.

Conclusion: Dapsone topical gels are single phase gel systems where the drug is partially dispersed in the formulation. The enhanced understanding of the relationship of the Q3 characteristics of the single-phase dapsone gels to their in vivo-performance provided by the PBPK modeling research reported here, which is supported by data from numerous ANDAs, provide new insights that minimize the risk of potential differences in local or systemic BA for dapsone topical gel test products that meet the criteria for no significant difference in components and composition relative to the RS, and which establish Q3 sameness compared to the RS, such that evidence from a an IVRT BE study may be sufficient to mitigate the actual risks of failure modes for BE with these dapsone gels. The evidence from this PBPK modeling aligns with, and reinforces, the BE recommendations in draft PSGs for other topical gels and illustrates that those recommendations are also suitable these dapsone topical gels, without additional evidence from direct assessments of local and systemic BA from IVPT and in vivo PK BE studies, respectively. The PSGs for dapsone topical gels have been revised to reflect the Agency’s current thinking.

Acknowledgements: The contents of this abstract/poster reflect the views of the authors and should not be construed to represent the FDA’s views or policies. No official support or endorsement by the FDA is intended or should be inferred. The mention of commercial products, their sources, or their use in connection with material reported herein is not to be construed as either an actual or implied endorsement of such products by the FDA.