Kinetics of Clobetasol-17-Propionate in Psoriatic Lesional and Non-Lesional Skin Assessed by Dermal Open Flow Microperfusion with Time and Space Resolution

Abstract

PurposeTo evaluate the kinetics of topically applied clobetasol-17-propionate (CP-17) in lesional and non-lesional psoriatic skin when released from a commercially available low-strength cream using in vivo dermal open-flow microperfusion (dOFM).MethodsTwelve patients received Dermovate® cream (CP-17, 0.05%) on small lesional and non-lesional skin test sites for 14 days, once daily. On day 1 and 14, dOFM samples were continuously taken in the dermis for 24 h post-dose and analyzed by LC-MS/MS. Probe depths were assessed by 50 MHz ultrasound scanning.ResultsMixed-effects modelling identified skin condition, treatment duration and probe-depth as kinetics determining variables. The time- and depth-resolved intradermal data revealed (i) slower penetration of CP-17 into lesional than into non-lesional skin, (ii) normalized (faster) skin penetration after repeated dosing, and (iii) no CP-17 accumulation within the dermis independently of the skin condition.ConclusionsIntradermal investigation of a highly lipophilic drug released from low-strength cream was successfully performed by using dOFM and timely and spatially, i.e., probe-depth dependent, resolved kinetic data were delivered. These data support the assumption that the thickened psoriatic stratum corneum might act as trap compartment which lowers the skin penetration rate for lipophilic topical drugs.Electronic supplementary materialThe online version of this article (doi:10.1007/s11095-016-1960-y) contains supplementary material, which is available to authorized users.

Variability of Skin Pharmacokinetic Data: Insights from a Topical Bioequivalence Study Using Dermal Open Flow Microperfusion

“…Also Stagni et al did not find any correlation between the kinetics of dermal drug absorption and probe depth in a dMD study investigating iontophoretically delivered propranolol [13]. However, the apparent lack of a correlation between probe depths and logAUC values in our acyclovir dOFM data set is in contrast to results from a dOFM study with the highly lipophilic drug clobetasol-17-propionate, where minor probe depth differences of 0.2 mm were shown to have an apparent influence on the observed AUC values [19].…”

Discovery and Early Clinical Development of Isobutyl 1-[8-Methoxy-5-(1-oxo-3H-isobenzofuran-5-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxylate (LEO 39652), a Novel “Dual-Soft” PDE4 Inhibitor for Topical Treatment of Atopic Dermatitis

“…The reasons behind lacking clinical efficacy have been investigated in depth, and our belief is that this is related to low free drug exposure of the candidate, not predicted by the biopsy sampling technique . We believe translational biomarkers and more advanced methods such as dermal open flow microperfusion or MALDI imaging which can determine drug at site of the target are likely necessary to measure relevant skin concentrations. − …”

“…H NMR (300 MHz, DMSO-d 6 ) δ 8.46 (t, J = 1.8 Hz, 1H), 8.34 (dt, J = 1.6, 8.2 Hz, 1H), 7.94 (dt, J = 1.6, 7.5 Hz, 1H), 7.74 (t, J -methylpropanoate(28). A screw cap vial charged with compound 25 (20 mg, 0.062 mmol), DIPEA (12 mg, 0.094 mmol), 2-methylpropanoyl chloride (9.8 μL, 0.094 mmol), and DCE (0.5 mL) was shaken at rt overnight.…”

Dermal open flow microperfusion for PK-based clinical bioequivalence studies of topical drug products

“…Open flow microperfusion (OFM) is based on a membranefree probe design to be used for continuous sampling in different tissues (Bodenlenz et al, 2012;Pieber et al, 2012;Birngruber et al, 2013;Höfferer et al, 2015;Tiffner et al, 2017). dOFM is one specific OFM application which is optimized for dermal studies and which is CE-certified for use in clinical studies in the European Union (Bodenlenz et al, 2013).…”