Assessment of dermal bioavailability: predicting the input function for topical glucocorticoids using stratum corneum sampling

Andrea Pensado,Anita Mcgrogan,Richard H Guy,M Begoña Delgado-Charro,Annette L Bunge,K A Jane White

doi:10.1007/s13346-021-01064-8

Abstract

Predicting the dermal bioavailability of topically delivered drugs is challenging. In this work, minimally invasive stratum corneum (SC) sampling was used to quantify the delivery of betamethasone valerate (BMV) into the viable skin. Betnovate® cream (0.1% w/w BMV) was applied at three doses (2, 5, and 10 mg cm−2) to the ventral forearms of 12 healthy volunteers. The mass of drug in the SC was measured using a validated tape-stripping method (a) after a 4-h “uptake” period, and (b) following a 6-h “clearance” period subsequent to cream removal. Concomitantly, the skin blanching responses to the same doses were assessed with a chromameter over 22 h post-application. BMV uptake into the SC was significantly higher for the 5 mg cm−2 dose compared to those of 2 and 10 mg cm−2. In all cases, ~30% of the drug in the SC at the end of the uptake period was cleared in the subsequent 6 h. From the SC sampling data, the average drug flux into the viable epidermis and its first-order elimination rate constant from the SC were estimated as 4 ng cm−2 h−1 and 0.07 h−1, respectively. In contrast, skin blanching results were highly variable and insensitive to the dose of cream applied. The SC sampling method was able to detect a 50% difference between two applied doses with 80% power; detection of a 20% difference would require a larger sample size. SC sampling enabled quantitative metrics describing corticosteroid delivery to the viable epidermis to be determined.Graphical abstract

Highlights

The pharmacodynamic response to a topically applied drug is determined by both its potency and its pharmacokinetics at the site of action in the skin [1,2,3,4]
The principal objective of the research presented in this paper is to examine whether the stratum corneum (SC) sampling method and data analysis approach outlined above provides an objective tool with which to quantify and permit the predictive modelling of corticosteroid BA in the skin following topical dosing
The vasoconstriction observed was highly variable, an unsurprising outcome given that the volunteers had not been pre-screened to confirm their ability to meet the criteria for inclusion in a formal vasoconstriction assay as defined by the regulatory guidance [17, 18, 30, 34]

Summary

Introduction

The pharmacodynamic response to a topically applied drug is determined by both its potency and its pharmacokinetics at the site of action in the skin [1,2,3,4]. The latter reflects the Department of Pharmacy & Pharmacology, University of Bath, Bath, UK. The input process comprises release from the applied formulation, partitioning into the stratum corneum (SC) and diffusion through the barrier to reach the viable epidermis and dermis where the target glucocorticoid receptors are located [9, 10]. Initial work with the method was directed at using the amounts of drug in the SC at uptake and clearance as potential metrics for the assessment of equivalence between

Methods

Results

Discussion

Conclusion