A draft guideline from the European Medicines Agency (EMA) highlights the need for methods to assess the quality/equivalence of topical drug formulations. The “cutaneous biodistribution method”, which provides insight into a drug’s spatial distribution in the epidermis/dermis, was used to compare cutaneous bioavailability of econazole nitrate (ECZ) from a reference medicinal product (RMP) and two approved bioequivalent generic creams under finite dose conditions. Statistically significant differences between the ECZ biodistributions from the RMP/Generics were determined and used with acceptance criteria based on those from the EMA to evaluate bioequivalence. In porcine skin, ECZ deposition in total skin, epidermis, upper and lower dermis from Generic 1 was within the acceptance interval, contrary to Generic 2, which was marginally below it. For human skin, Generic 1 deposition was marginally above the acceptance interval and not bioequivalent. The results were consistent with those using the EMA’s acceptance intervals using the ratio of the mean ECZ depositions of Generic 1 and the RMP. Differences identified using this data-rich technique may not translate to observable differences in clinical efficacy; however, generics with non-statistically different biodistributions to the RMP should have a comparable clinical effect. The cutaneous biodistribution method could benchmark the development of topical generic products.
The aim of this study was to investigate whether subtle differences in molecular properties affected polymeric micelle characteristics and their ability to deliver poorly water-soluble drugs into the skin. D-α-tocopherol-polyethylene glycol 1000 was used to prepare micelles containing ascomycin-derived immunosuppressants—sirolimus (SIR), pimecrolimus (PIM) and tacrolimus (TAC)—which have similar structures and physicochemical properties and have dermatological applications. Micelle formulations were prepared by thin-film hydration and extensively characterized. Cutaneous delivery and biodistribution were determined and compared. Sub-10 nm micelles were obtained for the three immunosuppressants with incorporation efficiencies >85%. However, differences were observed for drug loading, stability (at the highest concentration), and their in vitro release kinetics. These were attributed to differences in drug aqueous solubility and lipophilicity. Differences between the cutaneous biodistribution profiles and drug deposition in the different skin compartments pointed to the impact of differences in thermodynamic activity. Therefore, despite their structural similarities, SIR, TAC and PIM did not demonstrate the same behaviour either in the micelles or when applied to the skin. These outcomes indicate that polymeric micelles should be optimized even for closely related drug molecules and support the hypothesis that drugs are released from micelles prior to skin penetration.
Average (bio)equivalence tests are used to assess if a parameter, like the mean difference in treatment response between two conditions for example, lies within a given equivalence interval, hence allowing to conclude that the conditions have 'equivalent' means. The two one-sided tests (TOST) procedure, consisting in testing whether the target parameter is respectively significantly greater and lower than some pre-defined lower and upper equivalence limits, is typically used in this context, usually by checking whether the confidence interval for the target parameter lies within the same limits. This intuitive and visual procedure is however known to be conservative, especially in the case of highly variable drugs, where it shows a rapid power loss, often reaching zero, hence making it impossible to conclude for equivalence when it is actually true. This motivated the development of more powerful procedures. Here, we propose a finite sample correction of the TOST procedure, the α-TOST, which consists in an adjustment of the level of the TOST allowing to guarantee a type-I error rate of α. This new procedure essentially corresponds to a finite sample and variability adjustment of the TOST procedure. We show that this procedure, also appealingly relying of the assessment of equivalence by means of confidence intervals, is uniformly more powerful than the TOST, easy to compute, and that its operating characteristics are better that the ones of its competitors. A case study about Econazole Nitrate deposition in porcine skin is used to illustrate the benefits of the proposed method and its advantages compared to other available procedures.
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