Values of fluorescence using the 405-nm probe (A), the 632-nm probe (B), and as measured by the photo camera (C). Laser refers to the fractional ablative carbon dioxide laser. The horizontal line in the box indicates median; the box, interquartile range; error bars, minimum and maximum values; and open circles, eventual outliers.
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Bahadoran P, Le Duff F, Pascual T, et al. Comparative Methods for Improving Transepidermal Methylaminolevulinate Delivery: A Randomized Clinical Trial. JAMA Dermatol. 2015;151(12):1371–1373. doi:10.1001/jamadermatol.2015.2234
Penetration through the skin barrier is well known to be a challenge in the development of new drug formulations. Microneedling and ablative fractional lasers are reported1-3 to have a positive effect on skin penetration and increase of 5-aminolevulininc acid and methylaminolevulinate uptake but, to our knowledge, these methods have never been compared with each other. Fewer data exist concerning the potential interest of using occlusion for enhancing 5-aminolevulininc acid or methylaminolevulinate uptake. A multicenter prospective study4 using blue-light 5-aminolevulininc acid photodynamic therapy suggested that occlusion could increase the efficacy of the procedure. Although the therapeutic interest of using pretreatment for enhancing drug penetration into the skin is now clearly demonstrated, at least for photodynamic therapy, the relative effectiveness and tolerance of available procedures remains unknown.
We performed a prospective interventional, single-center, randomized clinical trial involving healthy volunteers to compare the effect on methylaminolevulinate penetration into the skin following various mechanical penetration enhancement techniques. The study was approved by the local ethics committee (CPP Sud Méditerranée V). The study protocol is available in the Supplement. The study was conducted from February 17 to May 9, 2014; data analysis was performed from June 27 to August 25, 2014. Ten healthy volunteers were included (Figure 1). The participants provided written informed consent and received financial compensation. At baseline, minizones of 4 cm2 on the participants’ backs were selected and randomly assigned to pretreatment: 3 minizones received microneedling (Derma Roller; Derma Roller System Ltd) with 12 passes to cover 2.5% of the surface, 3 received ablative fractional carbon dioxide laser (Fraxel re:Pair, 135-µm handpiece, 5 mJ, 2.5% surface coverage; Solta Medical), and 3 received no pretreatment. Laser parameters were adapted to the depth of the holes (expected to be approximately 0.2 mm), and surface coverage would be comparable to that of the microneedling. After pretreatment, methylaminolevulinate cream (Metvixia; Galderma) was applied on the 6 assigned minizones for 3 hours’ incubation. Each condition was tested with and without occlusion. The 3 minizones with no product applied were used for biophysics measures: transepidermal water loss, optical coherence tomography (Skintell; Agfa Health-Care), and reflectance confocal microscopy (VivaScope 1500; Mavig GmbH). Pain and tolerance were assessed immediately after pretreatment using simplified 4-point scales (pain: 1, none; 2, mild; 3, moderate; 4, severe; irritation: 1, none; 2, slight; 3, moderate; 4, severe). Analysis of fluorescence, measured with a dosimeter and reflex camera (Tewameter TM300; Courage & Khazaka), was performed using a mixed model at each time point with pretreatment and occlusion or not as fixed factors, the basal level of fluorescence as covariate, and the position on the back of the participant (high, medium, low) as random factors. The 3 pretreatments were compared with the Tukey multiple comparison test using the .05 level of significance.
Twelve individuals were screened for inclusion in the study, and 10 (8 men [80%] and 2 women [20%]; all were white) were included and randomized. Two individuals were excluded (1 had hyperhidrosis on the back and 1 had prohibited treatment). Ten patients completed the study and were included in the intention-to-treat and per protocol analyses. No participant was lost to follow-up (day 3 ± 1). The mean age was 41.5 years (range, 29-58 years). Two participants had Fitzpatrick skin type II and 8 were skin type III. Both microneedle and fractional ablative carbon dioxide laser pretreatment increased fluorescence compared with the nonpretreated zones (Figure 2). The difference was statistically significant after 1 hour of incubation (P < .001) and after 0.5 hours of incubation (P < .001) with the 405-nm and 632-nm probes, respectively. No significant difference was noted between the 2 types of pretreatment at the measurement performed at each time point with each technique (P > .24). Occlusion did not increase fluorescence in any of the conditions. Persistent channels were observed in reflectance confocal microscopy and high-density optical coherence tomography with ablative fractional carbon dioxide laser compared with the microneedle pretreatments. Transepidermal water loss was significantly higher with use of ablative fractional carbon dioxide laser compared with microneedles (P < .001), and both the laser and microneedles produced a level of transepidermal water loss higher than that of nonpretreated skin (both P < .001). Mild symptoms of pain were reported with microneedle pretreatment; moderate pain (severe for 1 patient) was reported with the laser pretreatment. No to slight signs of irritation were noted with the microneedle pretreatment, and moderate to severe signs of irritation were observed after laser pretreatment.
Ablative fractional carbon dioxide laser and microneedle pretreatment significantly and similarly enhanced the delivery of methylaminolevulinate into the skin, whereas occlusion did not induce a significant difference compared with the same conditions without occlusion. Although the differences were slight, this laser administration resulted in more transepidermal water loss and persistent channels observed on reflectance confocal microscopy and high-density optical coherence tomography compared with microneedle pretreatment. The pain associated with the use of microneedles was mainly absent or mild but was assessed as moderate to severe with use of the laser. These results bring useful information for improving photodynamic therapy and provide insights for enhancing drug penetration into the skin.
Accepted for Publication: June 5, 2015.
Corresponding Author: Thierry Passeron, MD, PhD, Department of Dermatology, University Hospital of Nice, 150 route de Ginestière 06202, Nice, France (email@example.com).
Published Online: September 9, 2015. doi:10.1001/jamadermatol.2015.2234.
Author Contributions: Drs Bahadoran and Le Duff contributed equally to this work. Dr Passeron had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Bahadoran, Le Duff, Pascual, Petit, Martel, Passeron.
Acquisition, analysis, or interpretation of data: Bahadoran, Le Duff, Pascual, Petit, Lacour.
Drafting of the manuscript: Le Duff, Pascual, Passeron.
Critical revision of the manuscript for important intellectual content: All authors.
Obtained funding: Pascual, Martel.
Administrative, technical, or material support: Bahadoran, Le Duff, Pascual, Martel, Lacour.
Study supervision: Pascual, Passeron.
Conflict of Interest Disclosures: Drs Bahadoran, Lacour, and Passeron received honoraria for lectures and grants for studies from Galderma. Drs Pascual, Petit, and Martel are employees of Galderma. No other disclosures were reported.
Funding/Support: This study was supported in part by Galderma Research and Development, Clinical Unit for Tests and Imaging of Skin.
Role of the Funder/Sponsor: The sponsor contributed to the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, and approval of the manuscript; and decision to submit the manuscript for publication.
Trial Registration: clinicaltrials.gov Identifier: NCT02511145.
Additional Contributions: We are indebted to Bastien Gamboa, MS, Valérie Bourdès, MD, and Philippe Andres, MD (Galderma R&D), for their help collecting and analyzing the data. There was no compensation in addition to salary.