Description
Background:Although physiologically-based pharmacokinetic (PBPK) modeling is a methodology introduced in the 1940's, recent advancements in computation and an expanding body of experimental in vivo/in vitro data have rendered it an important tool in the drug development process. PBPK models are distinctly different from conventional pharmacokinetic models due to their unique structure. They are comprised of system-dependent parameters that include species-specific anatomy and physiology information (i.e. tissue volume, blood flow, glomerular filtration rate, plasma protein and enzyme abundance) and of drug-dependent parameters such as physicochemical properties (molecular weight, solubility, pKa and logP among others). This "bottom-up" approach encompasses a mechanistic description of the processes of absorption, disposition and elimination of administered compounds via oral and non-oral routes.Utilizing PBPK modeling for complex drug products that are applied on the skin to treat a disease condition locally, and/or after reaching the systemic circulation, is an approach that has gained attention in the recent years. Leveraging information on skin physiology and incorporating compound- and formulation-specific characteristics could lead to the development of dermal PBPK models intended to predict drug amounts in different skin layers. Importantly, the mechanistic nature of dermal PBPK models enable clinical pharmacologists to identify model parameters related to skin physiology, drug substance properties and formulation critical quality and performance attributes that may impact the local or systemic bioavailability of the drug and assess their clinical relevance. This is critical for generic drug development since generic drugs have the same indication as the innovator drug products, but differ in their formulation. Ideally, a well-qualified dermal PBPK model may be leveraged to simulate virtual bioequivalence trials to assess bioequivalence between the generic drug product and its innovator (reference) drug product.Topical dermatological products act locally, and local tissue concentrations at the site of action is a critical component in determine bioequivalence for such products. However, such data is not readily available or even measured for most products. Additionally, topical administration typically does not lead to quantifiable drug concentrations in the systemic circulation, rendering bioequivalence evaluation a challenging process for these complex dosage forms. Transdermal delivery systems face also challenges in their development process since their absorption into the systemic circulation is mediated via a complex organ, the skin.The quality of the pharmaceutical dosage form is a critical factor for consistent and desirable in vivo performance of dermatological drug products. Aspects of the drug product that are assessed during therapeutic bioequivalence assessments (in vitro approach outlined in certain Product-specific Guidance) include whether the same components (qualitatively same, Q1) at a similar concentration (quantitatively same, Q2) are present between the brand name and the generic drug product and whether there are similarities in the arrangement of the matter/microstructure (Q3) within the dosage form between innovator and generic drug product. An approach typically followed in the drug product development process is the quality by design which is a useful tool in monitoring and improving product quality. Integral part of that process is identifying critical quality and performance attributes for drug products that are defined as physicochemical, biological and microbiological properties or characteristics that are expected to be within defined limits or distributions to ensure desired and consistent product quality.PBPK modeling allows predictions of local and systemic API concentrations following the integration of in vitro measurements on critical quality and performance attributes directly into the model structure or by establishing in vitro-in vivo correlations (IVIVCs) for drug products for which in vitro data on formulation characterization and pharmacokinetic data are available. These correlations can be leveraged to predict in vivo performance of similar formulations for which only in vitro data is available. For these reasons, dermal PBPK modeling is an extremely useful tool in the drug development process, in the interaction with regulatory agencies, and in decision making in the clinical setting.Objectives:The main objective of the current funding opportunity is to incorporate drug product quality attributes into dermal physiologically-based pharmacokinetic models developed for dermatological topical dosage forms and transdermal delivery systems. The developed models will be utilized to identify drug-product specific critical quality and performance attributes (model qualification) and perform virtual bioequivalence assessments between brand name and generic drug products to inform regulatory decisions relating to the development of dermatological drug products.Detailed description:A proposed approach aiming at meeting the objectives outlined above is detailed below.1. Conduct extensive (literature) search to identify quality and performance formulation attributes for dermatological products of interest.These might include, but not be limited to: crystallization, phase separation, sedimentation, rheology/viscosity change, color/odor change, volatility, mixing time/type/speed, temperature change, physical observation, smoothness, level and type of antimicrobials, antioxidants and chelating agents, endogenous preservatives, uniformity, pH, dissolution, globule size and distribution, in vitro release, in vitro skin permeation and adhesion properties, and excipients. Potential critical quality and performance attributes for the API might include, but not be limited to: solubility, melting point, salt or base, particle size, polymorphism, liquid or solid form, degree of saturation or supersaturation, and crystal habit.Additional critical quality and performance attributes for specific skin drug products might be identified in collaboration with the FDA research team to address regulatory needs.2. Retrieve information on quality and performance formulation attributes for dermatological products of interest from several independent and accredited literature sources (peer review articles, textbooks, etc.), by utilizing in house data if available or by designing and conducting studies that would allow the generation of the necessary experimental data in special populations of interest. Organize the retrieved information in an easily accessible database.3. Develop dermal PBPK models for topical and transdermal dosage forms that incorporate the previously collected information on quality and performance formulation attributes of dermatological products of interest.The dermatological drug products that will be selected for dermal PBPK model development should be able to cover a wide variety of APIs in terms of their physicochemical properties and permeability. Physicochemical properties of an API impact formulation stability, API release from the formulation when applied into the skin and partitioning through the different skin layers while being absorbed. Therefore, this research project could benefit from modeling APIs of distinctly different solubility, pKa and permeability (logP) profiles. Although not a requirement for the selection process of API to be studied, a Biopharmaceutics Drug Classification-like approach (Pharm. Res. 1995 Mar;12(3):413-20) in selecting API candidates for dermal PBPK model development will be welcomed. The Office of Generic Drugs recognizes the critical role of the formulation on the in vivo performance of a drug product. Therefore, dermatological dosage forms that could be of interest in the model development process include, but are not limited to: creams, ointments, gels, emulsions, suspensions, lotions, solutions, films and patches.Additional dosage forms and drug products (formulations) might be identified in collaboration with the FDA research team to address regulatory needs.4. Validate/qualify the previously developed dermal PBPK models utilizing appropriate datasets retrieved from independent and accredited literature sources, utilize in house data if available or design and conduct studies that would allow the generation of the necessary experimental datasets.Appropriate datasets that capture the subpopulation, study design and dosage form, and quality and performance attributes of the drug product that were incorporated in the model are expected to be utilized for model validation/qualification.5. Utilize the developed, qualified models to evaluate bioequivalence for generic drug formulations by simulating virtual bioequivalence studies. Multiple scenarios should be simulated to demonstrate model flexibility, sensitivity and overall predictability.