. This project responds to the Funding Opportunity, RFA-FD-16-028, ?Bioequivalence of Topical Products: Comparing Dermal Pharmacokinetics by Microdialysis or Microperfusion Techniques? (U01). The continuous in- vivo measurement of drug concentrations in the dermis by either dermal microdialysis (dMD) or dermal open flow microperfusion (dOFM) is a direct approach to monitor the rate and extent to which a topically administered drug becomes available at or near the site of action (in the dermis). This approach can compare the bioavailability of a topically administered drug from test and reference products with that in healthy skin (subjects) or in diseased skin (patients). The goal of this proposal is to determine the suitability of the microdialysis technique to assess topical bioequivalence. While numerous studies support the utility of dMD for such purpose, they also point out several limitations like high variability in the results, dermal drug concentrations too low to quantify, study durations too brief for adequate comparison of the products (e.g. only 4-5 hours), subject discomfort during probe insertion, and extended immobilization of study participants. In this study, we propose new strategies to overcome such limitations. The proposed research project consist of two parts. First, we will optimize variables such as subject inclusion/exclusion criteria, topical dose size and duration of applications, and dermal sampling duration and frequency. Here we will also investigate the use of intermittent microdialysis as an alternative or complementary approach to continuous microdialysis as well as the possibility to leave the probes on overnight to better characterize the entire dermal pharmacokinetic profile. We will also evaluate the utility of correction factors such us probe depth measurements, perfusate internal standard compounds, trans-epidermal water loss (TEWL), and limb blood flow. We will use both positive and negative controls, selected in agreement with the FDA, from either commercially available formulations or specifically in-house compounded formulations. A major goal of this first part of the project is to understand the distribution/elimination of the selected drug in the dermis. We anticipate that possible variability in these processes may contribute to the observed noise in dMD data and therefore filtering it will provide cleaner measurements of the significant data. Hence, these studies will yield basic information about the variability of the methodology and will identify the optimal number of subjects/measurements necessary to reach statistical significance in bioequivalence assessments. The expected outcome of this part of the study is the rational identification of optimal criteria to be used in subsequent studies. In the second part of the project, we will perform bioequivalence studies according to the optimized conditions determined in the first part. We will test (i) the reference product versus itself, (ii) a generic version of the reference versus the reference, and (iii) a very different product (e.g., double strength) versus the reference. In these studies the data analyst(s) will be blind. All studies will be performed according to GLP and GCP.
The proposed project is an in-depth benchmark of the utility of microdialysis to assess bioequivalence of topical dermatological products and will advance knowledge of the pharmacokinetics of drugs in the dermis. This will be driven by a complete characterization of the concentration profiles in dermis, including the elimination phase. The significance of the project is that: (1) it will yield a comprehensive baseline measurement and understanding of the intrinsic variability in drug permeability through the skin as measured with dMD; (2) it will exercise and fine-tune appropriate statistical tools to identify the optimal number of subjects/measurements required to assess either similarity or dissimilarity of topical dermatological products; and (3) this understanding will assist in the development of guidance for the design of BE studies of topical dermatological products based on the microdialysis technique.