Development of a pharmacokinetic model for skin absorption

The evaluation of equivalence between topical drug products is challenging. Unlike oral administration, the relationships of critical quality attributes to in vitro performance and of in vitro performance to in vivo safety, efficacy and clinical performance are, at best, poorly defined. The central hypothesis of the project Development of a pharmacokinetic model for skin absorption is that a relevant and testable physiologically-based (PB) absorption and pharmacokinetic (PK) model is able to capture and shed light upon the complex interplay between product attributes and patient outcomes in vivo. Topical drug products are complex, multicomponent systems, the properties of which change profoundly post-application to the skin. For example, a common aqueous-based vehicle or cream likely contains, in addition to the drug, water, one or more co-solvents, a polymeric gelling agent, a volatile solvent, emulsifiers or surfactants to stabilise a disperse system as well as other ingredients to render the formulation cosmetically and pharmaceutically acceptable. Consequently, drug absorption kinetics are difficult to simulate with a simple mathematical construct. A principal and novel specific aim, therefore, is to characterise the drug input process experimentally using a straightforward experimental approach. Known drug input rates from transdermal patches will be used to validate, refine and optimise the robustness of the developed experimental approach to characterise the drug input function correctly, permitting the subsequent application of the model to the investigation of a broad spectrum of complex topical drug products. A further specific aim, therefore, is the application of the optimised experimental methodology to determine drug input functions from typical products such as creams, ointment and gels. As opposed to transdermal patches, the modeling of drug input into the skin from classical topical formulations has never accurately reflected the reality of the product metamorphosis that occurs during its application and massage into the skin. Thus, a proper understanding of the `metamorphosis` of the vehicle once it is applied to the skin is necessary. With the help of non-invasive Raman spectroscopy, valuable information about the metamorphosis of topical formulations as they are massaged into the skin and transform from the prepared vehicle to the residual surface film will be gained. Ultimately, the development, validation and application of a PBPK model for dermal drug absorption would represent a major step forward in regulatory science and would further lead to a significant reduction or even elimination of the dependency on animal models and human studies, accelerating the drug development process and bringing safe and effective products to market more rapidly and economically.

It has proven difficult to predict whether a drug applied in a typical skin product, such as a cream, ointment or gel, reaches an effective concentration in the viable skin. In order to reach its target site in the viable skin, a drug firstly needs to overcome the outermost layer of the skin, the stratum corneum. The dead cell layers of the stratum corneum can be removed with adhesive tapes by a minimally invasive technique called tape-stripping. This method can be used to obtain information about drug uptake from a formulation. By delaying tape-stripping post-removal of the formulation, it should also be possible to assess drug clearance from the stratum corneum, allowing estimation of how much drug diffuses into the deeper layers of the viable skin below during a fixed period of time. This project aimed to test this idea by comparing the input of nicotine and lidocaine into the viable skin following application of commercialised transdermal patches using tape-stripping in vivo. Transdermally delivered drugs are not intended to target structures within the skin, but provide valuable information about a drugs journey from the skin surface to the blood. The known input rates of transdermal nicotine and lidocaine delivery systems were used to validate and assess a tape-stripping protocol that can duplicate the claimed input rates. The determined drug input rates from tape-stripping agreed well with the claimed delivery rates on the patch labels. Related to applying the method of tape-stripping to characterise the input from typical topical products, the input of lidocaine into the skin was also determined from a commercialised cream product. Tape-stripping in vivo revealed differences in the drug input rate between the cream and the patch. All in vivo results were compared to those obtained more conventionally in vitro using diffusion cells and pig skin. The different input rates between drugs and formulations were confirmed qualitatively and quantitatively in vitro. A further step towards determination of drug input into the skin was made by using the non-invasive technique of Raman spectroscopy to successfully characterise the phenomenon of nicotine clearance from the stratum corneum.In conclusion, the results support the hypothesis that drug input into the viable skin from a topical formulation can be estimated using stratum corneum tape-stripping at judiciously selected uptake and clearance times. Experimentally obtained information about the input function into the viable skin should now feed into a mathematical model to predict drug concentration in the viable skin. Successful prediction of drug levels at the site of action in the viable skin would be a crucial step towards accelerating the drug development process and bringing safe and effective products to the market more rapidly and economically.