Dermal Drug Product Quality and Bioequivalence Assessment through Advanced MAM and PBPK Simulation

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Abstract - Dermal Drug Product Quality and Bioequivalence Assessment Through Advanced MAM and PBPK Simulation The Office of Generic Drugs (OGD) is tasked with reviewing sponsor applications for dermal dosage forms that purport to be bioequivalent to reference listed products for the same active dosage forms. Sponsors need to have high confidence that the applications they submit for dosage forms which are thought to be bioequivalent will receive favorable reviews. Software that implements physiologically based pharmacokinetics (PBPK) and mechanistic absorption modeling (MAM), and accounts for formulation effects in predicting local drug concentrations in both the skin and systemic circulation can be a useful tool in reducing the time and expense involved in designing new generic formulations by assessing their potential to be bioequivalent to currently approved dosage forms by industry and regulatory scientists. The proposed project will advance the state-of-the-art for dermal MAM/PBPK modeling in the Transdermal Compartmental Absorption and Transit (TCAT™) MAM/PBPK model within the GastroPlus® and MembranePlusTM software applications by incorporating more detailed descriptions of (i) the temporal evolution of drug thermodynamic activity and transport in formulations as their components are absorbed into the skin or lost to evaporation; and (ii) normal and pathological skin physiologies; particularly as they relate to percutaneous permeation. Specifically, we seek to add models for active metabolism and transport of drugs and pro-drugs, binding to melanin and keratin, and enhancement of drug permeation by a formulation excipient (chemical permeation enhancement). New formulation types (e.g. solid lipid nanoparticles and nanostructured lipid carriers) will also be added to the TCAT™ model. Finally, the virtual bioequivalence simulator in GastroPlus® will be expanded to more comprehensively reflect formulation variability and skin physiological variability, and to include bioequivalence comparisons of formulations based on local skin concentrations in addition to systemic concentrations. Advancing the state-of-the-art for dermal MAM and PBPK simulation requires a comprehensive knowledge base to serve as the scientific foundation that talented scientists can apply in order to develop useful equations and logic suitable for software; high-level computer programming skills to encode the equations and logic into the software; and experienced scientists to test, validate, document, and support the software for general use. Throughout these efforts, we will maintain close contact with both the FDA and our collaboration partners in order to ensure that the project team focuses on the software developments needed for implementation of dermal product Quality by Design (QbD) and virtual bioequivalence assessments according to the scope of the project.