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

Manfred Bodenlenz, Christian Dragatin, Lisa Liebenberger, Bernd Tschapeller, Beate Boulgaropoulos, Thomas Augustin, Reingard Raml, Christina Gatschelhofer, Nathalie Wagner, Khaled Benkali, Francois Rony, Thomas Pieber, Frank Sinner, Manfred Bodenlenz, Christian Dragatin, Lisa Liebenberger, Bernd Tschapeller, Beate Boulgaropoulos, Thomas Augustin, Reingard Raml, Christina Gatschelhofer, Nathalie Wagner, Khaled Benkali, Francois Rony, Thomas Pieber, Frank Sinner

Abstract

Purpose: To 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).

Methods: Twelve 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.

Results: Mixed-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.

Conclusions: Intradermal 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.

Keywords: dermal pharmacokinetics; lipophilic drug; open flow microperfusion; skin penetration; topical formulation.

Figures

Fig. 1
Fig. 1
Left: Scheme of dOFM setup. The membrane-free dOFM probe within the dermis is continuously perfused and delivers interstitial fluid for further analysis. Right: Wearable dOFM setup including the dOFM probe, a wearable push-pull pump, and a unit for sample collection.
Fig. 2
Fig. 2
Study days with treatment regimen and protocol on the days of OFM investigation. CP-17 was dosed as Dermovate® Cream 0.05% once daily from day 1 to day 14. Following the doses on day 1 and day 14 the kinetics of CP-17 were followed in dermal interstitial fluid for 24 h by using dOFM.
Fig. 3
Fig. 3
Mean CP-17 concentration profiles from baseline to 24 h post-dose on the Day 1 (after 1st dose) and Day 14 (after 14th dose). (a) Non-lesional skin profiles. (b) Lesional skin profiles. Data are mean ± sem.
Fig. 4
Fig. 4
AUC data of non-lesional skin on day 1 plotted versus depth. Regression lines are fitted to the AUCs of the 3 adjacent probes in non-lesional skin for each subject. The illustration indicates a relationship between the AUCs and probe depth in 7 of 8 subjects (negative slopes) and also indicates that most of the variability is due to inter-subject variability of CP-17 penetration.
Fig. 5
Fig. 5
AUC0-24 h for CP-17 in dOFM samples on the days 1 and 14 as a function of depth. (a) AUCs of non-lesional skin and (b) AUCs of lesional skin; (c) All four AUC regression lines from both non-lesional and lesional skin on both day 1 and day 14 (see Eqs. 1–4).

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Source: PubMed

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