Evaluation of in-vitro and ex-vivo methods for bioequivalence testing of topically applied dermatological drug products

Katrin Tiffner

Publikation: StudienabschlussarbeitDissertation


For topically applied, dermatological drug products (e.g. creams) acting locally in the skin, bioequivalence (BE) evaluations are challenging as few established methods exist to evaluate its local bioavailability at the site of drug action, in the dermis. Hence, the majority of topically applied generic drug products are tested in cost intensive clinical endpoint studies. As these studies possess a low sensitivity and show higher variabilities, a large patient population is needed in order to demonstrate BE. To overcome these limitations FDA has been funding several research projects to promote the development of sensitive and discriminating methods for BE evaluations of topically applied dermatological drug products. Within this collaborative research project dermal open flow microperfusion (dOFM) was evaluated as a possible method for BE testing in a clinical study using healthy subjects and in an ex-vivo study using excised human skin samples. Further, a comparative in-vitro release testing IVRT study was conducted to evaluate the ability of IVRT as surrogate for clinical BE testing.
The aim of the herein described doctoral thesis was the development and implementation of the IVRT and ex-vivo study using different acyclovir products. Additionally, results from the in-vitro and ex-vivo study were compared with data obtained in the clinical dOFM study.
To get reliable and reproducible IVRT results, a comprehensive qualification and validation protocol for the IVRT system was developed. After the IVRT system was successfully qualified and validated, a IVRT study was conducted to compare the release rates of six different, already marketed acyclovir products against the reference product Zovirax cream 5% U.S.. Results of the comparative IVRT study showed that with the qualified and validated IVRT system, qualitatively and quantitatively different cream products can be successfully distinguished. Comparison of the IVRT data with data obtained in the clinical dOFM study showed that IVRT cannot predict the clinical results. Nevertheless, IVRT is a sensitive and reproducible method to detect differences in the composition of products that might cause differences in their in-vivo performance.
In the ex-vivo study, 40 skin samples were used to compare the dermal pharmacokinetic (PK) of a topically applied reference product against itself (positive BE control) and against an in-equivalent test product (negative BE control). The ex-vivo study was designed similar to the clinical study to allow a valid comparison between ex-vivo and in-vivo data. Due to high variabilities in the ex-vivo study, the positive control failed the BE test when the commonly applied average BE (ABE) statistical approach was used. However, when using the reference-scaled ABE (RSABE) approach, BE of the positive control was confirmed. Results suggest the RSABE approach may be a more appropriate statistical method for BE testing of topical applied dermatological drug products as local differences of the skin characteristic might increase the variabilities in the obtained dermal PK data. The negative control failed the BE test using both statistical approaches (ABE and RSABE) and results were comparable with the clinical study. In conclusion, the ex-vivo model can provide preliminary results for BE evaluations.
QualifikationDoktor der Technik
Gradverleihende Hochschule
  • Technische Universität Graz (90000)
Betreuer/-in / Berater/-in
  • Scharfetter, Hermann, Betreuer
  • Sinner, Frank, Betreuer, Externe Person
PublikationsstatusVeröffentlicht - 2020


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