Dermal pharmacokinetics of topical and transdermal drugs and their PBPK modeling
Creators: name: Matharoo, Namrata S.
Publisher: name: No Publisher Supplied
Year: 2025

description: Transdermal drug delivery (TDD) has been an attractive route of drug administration for many years and has been proven to have higher patient compliance when compared to oral and needle-based administration. TDD provides several advantages over other administration routes such as patient self-administration, non-invasive therapy, reduced side effects, and much reduced toxicity due to low systemic exposure. Over the years, remarkable advancements have been made in TDD with successfully delivering certain hormones and drugs such as siRNAs, peptides, and others, which are often degraded in the gastrointestinal tract when administered orally.Despite the advancements in TDD, the administration technique has still not reached its full potential. It has been relatively challenging to study the pharmacokinetics of the drugs administered topically. This has been mainly due to the limited ability of drugs to cross the stratum corneum (SC), the outermost layer of the skin. SC is made up of dead keratinocytes (corneocytes) surrounded by lipid matrix. This architecture of SC is commonly known as the “brick and mortar” model, where the bricks represent the corneocytes and the mortar the lipid matrix. Although this is the thinnest layer of the skin, it is the toughest. Its primary function is as a physical barrier to prevent the entry of foreign compounds into the body. Due to this barrier effect, it is challenging to deliver adequate amounts of drugs across the SC. Due to some recent advancements, the barrier of the stratum corneum has been overcome to some extent with various approaches such as chemical and physical enhancement techniques. However, due to limited drug absorption and perfusion into the systemic circulation, many of the commonly used analytical methods are not able to successfully quantify extremely low drug levels that are required for plasma concentration-time profiles. Therefore, conventional pharmacokinetic models cannot be employed to determine the pharmacokinetic parameters. The goal of this project is to study the dermal pharmacokinetics of drugs to parameterize, optimize, and validate dermal physiologically based pharmacokinetic (PBPK) models which can be used with the full-body PBPK model to predict and estimate the pharmacokinetic parameters that cannot be determined through in vitro or in vivo studies. The dermal PBPK model, which was initially built by our collaborator CFD Research Corporation (Huntsville, AL 35806, USA) was used in these studies. This multi-compartment dermal PBPK model incorporated the complex structure of the SC. This model integrates the drug release and ex vivo studies to optimize the mechanistic model. To conduct this project, two classes of drugs have been studied using “bioequivalent” formulations as deemed by the FDA – adapalene (topical application) and desoximetasone (transdermal application). Adapalene is a third generation retinoid which has a logP of 6.9. This lipophilic compound has a tendency to interact with the lipids in the SC and the sebum found in the pilosebaceous unit. It is primarily used for the treatment of acne vulgaris. Similarly, desoximetasone, which has a logP of 1.83 was studied with two formulations both available over the counter which are deemed to be “bioequivalent” by the FDA. These formulations were used to study the release kinetics of the drug in vitro. These release profiles were used to determine parameters such as permeability and diffusivity using the Brunner modification of the Noyes-Whitney equation. The use of the Noyes Whitney equation for modeling release studies is advantageous due to its origins in Fick’s laws of diffusion. This significantly simplifies the model by maintaining consistency and minimizing complexity across the compartment. In addition, this helps in minimizing potential errors and streamlining the analytical process and assists in fine tuning diffusivities and partitioning coefficients which are then leveraged into the dermal PBPK model.The ex vivo studies were conducted using human cadaver skin samples obtained from U.S. accredited skin tissue banks. These studies were employed to study the absorption, distribution and flux of the drugs using Fick’s law of diffusion. Fick’s law of diffusion describes the transfer of a drug from one compartment to another over time, separated by thin membrane/ skin of thickness “x” per unit area. Mathematically, the permeation flux can be written as: (Matharoo et al., 2024) Equation 1: Mathematical representation of Fick’s law of diffusion where:J is the fluxQ is amount of solute A is unit area of membrane/skin surfaceC is concentration of solutedx is thickness of membrane/skindC/dx is concentration gradient (Cs) t is timeThis equation indicates that the transport of drug is driven by the concentration gradient across two compartments (donor and receptor). The skin and receptor concentration-time profiles were determined over 24 to 36 hours. The skin layers were mechanically separated to study the cumulative distribution of drugs. The dermal PBPK model included the skin layers: SC, viable epidermis (VE) and dermis. The skin thickness and weights of skin used experimentally were used in the model to closely match the experimental data, providing robust platform and to study drug delivery and skin absorption dynamics. To study the effect of adapalene on acne disease, a comparative clinical study was performed in collaboration with Robert Wood Johnson Hospital. In this randomized study, the adapalene gels were applied on the malar cheek of the patients with mild to medium non-inflammatory comedones. The gels were reapplied every 24 hours in a 48-hour study. These studies gave us an insight into the effect of adapalene on the pilosebaceous unit and the SC. The changes in the size of these were studied to determine the effect on sebum degradation and unclogging the pilosebaceous unit and the desquamation rate of SC. A systems biology model for acne is currently being built using the information from the clinical study and the data from the literature. This model has the structure of the epidermis accounting for stratification of epidermis by incorporating the proliferation and differentiation of keratinocytes in the epidermis, connected with the sebaceous gland. Acne formation due to sebum production and dead cell accumulation in the pilosebaceous unit and its effect on bacterial growth and the innate immune system will be studied. The effect of bioavailable adapalene on these processes will be incorporated in this model by integrating the previous PBPK model.