(M1330-11-63) Quantitative Analysis to Discriminate Cutaneous Pharmacokinetic Profiles for Topical Drug Products

Purpose: Dermal open flow microperfusion (dOFM) has been used to measure the cutaneous pharmacokinetics (PK) of topical dermatological drug products. Previous research in this area has shown that the dOFM technique has the potential to support a demonstration of bioequivalence (BE) for prospective generic topical dermatological drug products. The dOFM method should be designed to be sensitive at discriminating the differences in cutaneous bioavailability of the drug substance (e.g., from different formulations or different dose amounts). The purpose of this study was to investigate quantitative analyses using the pilot study, to establish the discrimination sensitivity of cutaneous PK studies using dOFM.

Methods: Quantitative analyses were performed using a pilot study in six human subjects that compared the cutaneous PK of lidocaine and prilocaine from different products or doses using dOFM (Figure 1)¹. Analyses of average bioequivalence [ABE], reference scaled ABE [SABE], and an assessment of difference (f₁) and similarity (f₂) were evaluated for their ability to discriminate the cutaneous PK profiles from R (cream at 10 mg/cm²) and T treatments (various doses of the cream and gel) (Figure 2). Cutaneous PK profiles were considered to be discriminated if f₁ > 15 or f₂ < 50. A bootstrap analysis was also performed.

Results: The cutaneous PK profiles from the R and T treatments were quantitatively discriminated by all analyses, except for the cream at 10 compared to 15 mg/cm², which was not discriminated by SABE nor f₁/f₂ analysis. For the purpose of this study, the bootstrap analysis consistently discriminated all the R and T comparisons of PK profiles based on f₁ and f₂ 90% confidence intervals (Table 1).

Conclusion: The quantitative analyses were generally consistent with qualitative (visual) assessments of the PK profiles, however, the suitability of each analysis and the discrimination cutoff values need further evaluation. While an (S)ABE analysis of pilot study data would typically be under-powered, f₁/f₂-based quantitative analyses may be a practical way to establish the sensitivity of cutaneous PK studies, particularly if a bootstrap analysis is used to confirm the results.

References: 1. Tiffner K, Birngruber T, Schwargerle G, Bodenlenz M, Augustin T, Raml R, Kanfer I, Sinner F. Dermal pharmacokinetic endpoint studies to evaluate bioequivalence of topically applied lidocaine and prilocaine drug products. Poster session presented at: American Association of Pharmaceutical Scientists; 2019 Nov 3-6; San Antonio, TX.

Acknowledgements:Funding for this project was made possible, in part, by the U.S. Food and Drug Administration through grant 1U01FD005861. This project was supported in part by an appointment (Sagar Shukla) to the Research Participation Program at the FDA Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and FDA. The views expressed in this poster are those of the authors and should not be construed to represent FDA’s views or policies.


Figure 1. Diagram illustrating the study design


Figure 2. Concentration versus time profiles (mean ± SE, n=6 volunteers) from the dOFM pilot study (A: Lidocaine dermal concentrations, B: Prilocaine dermal concentrations).


Table 1. f1 and f2 analysis comparing lidocaine; prilocaine formulations to EMLA® cream 10 mg/cm2 using data from the pilot dOFM study and from a bootstrap analysis (n=1000).