Open Flow Microperfusion as a Dermal Pharmacokinetic Approach to Evaluate Topical Bioequivalence

Abstract

Background: The availability of generic topical dermatological drug products is constrained by the limited methods established to assess topical bioequivalence (BE). A novel cutaneous pharmacokinetic approach, dermal open-flow microperfusion (dOFM), can continuously assess the rate and extent to which a topical drug becomes available in the dermis, to compare in vivo dermal bioavailability (BA) and support BE evaluations for topical products.

Objective: To evaluate whether dOFM is an accurate, sensitive, and reproducible in vivo method to characterize the intradermal BA of acyclovir from 5 % acyclovir creams, comparing a reference (R) product either to itself or to a different test (T) product.

Methods: In a single-center clinical study, R or T products were applied to six randomized treatment sites on the skin of 20 healthy human subjects. Two dOFM probes were inserted in each treatment site to monitor the intradermal acyclovir concentration for 36 h. Comparative BA (of R vs. R and T vs. R) was evaluated based on conventional BE criteria for pharmacokinetic endpoints (area under the curve and maximum dermal concentration) where the 90 % confidence interval of the geometric mean ratio between the T and R falls within 0.80-1.25.

Results: The positive control products (R vs. R) were accurately and reproducibly confirmed to be bioequivalent, while the negative control products (T vs. R) were sensitively discriminated not to be bioequivalent.

Conclusions: dOFM accurately, sensitively, and reproducibly characterized the dermal BA in a manner that can support BE evaluations for topical acyclovir 5 % creams in a study with n = 40 (20 subjects in this study).

Conflict of interest statement

Compliance with Ethical Standards Funding Funding for this project was made possible, in part, by the FDA through research award FD004946. The views expressed in this publication do not reflect the official policies of the FDA, or the Department of Health and Human Services; nor does any mention of trade names, commercial practices, or organization imply endorsement by the United States Government. Conflict of interest MB, KIT, RR, BT, TA, CD, TB, SK, DS, TRP, and FS are employees of Joanneum Research holding patents on OFM devices. SGR is an employee of US FDA. GS and IK declare that there are no conflicts of interest. Ethics, informed consent, research involving human participants The study was conducted with the full informed consent of all participating subjects, under the authority of the Ethical Committee of the Medical University of Graz, the Austrian health authority AGES, and the FDA’s Research Involving Human Subjects Committee (RIHSC) and was performed in accordance with Good Clinical Practice and the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. The study has been registered in the European Clinical Trials Register (EudraCT No. 2013-005062-19) and at ClinicalTrials.gov (NCT02711267).

Figures

Fig. 1

Schematic of dermal open flow microperfusion

Fig. 2

Scheme (a) and photograph (b) of the duplicate test triad for comparative bioavailability assessment. Two treatment sites per test triad were dosed with the reference product (R1: central, R2: non-central) and one treatment site was dosed with the test product (T)

Fig. 3

Dermal open flow microperfusion (dOFM) acyclovir concentration profiles for the test product (T) site and the two reference (R1 and R2) sites (mean ± standard error of the mean, n = 40 test triads in 20 subjects). Acyclovir was analyzed from one pre-dose sample (spanning −1 to 0 h) and nine pooled post-dose samples (spanning 0–4, 4–8 … 32–36 h). The post-dose concentrations are plotted at the mid-point of the time intervals (2, 6 … 34 h)