Needling-Assisted Drug Delivery: Enhanced Response to Ingenol Mebutate After Microneedling

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Recent studies have shown that pretreatment of the skin with ablative fractional lasers, followed by photodynamic therapy (PDT), is a safe and effective technique to increase the bioavailability of topically applied methyl aminolevulinate, leading to an improved clearance rate of actinic keratosis (AK).1,2 Recently, Bencini and colleagues3 and Torezan and colleagues4 have shown that microneedling-assisted drug delivery (MADD) may also be an effective way to increase the efficacy of PDT. Following up on these concepts, our group has proposed that the benefits of laser-assisted drug delivery for the treatment of actinic field cancerization are not limited to PDT, but can also be applied to other drugs for the topical treatment of AK.5 Ingenol mebutate (IM) is a first-in-class macrocyclic diterpene ester, extracted and purified from the plant Euphorbia peplus, which is effective for field treatment of nonhyperkeratotic AK.
Here, we report the application of MADD to IM therapy of a 59-year-old female patient with actinic field cancerization. Four test fields (3 × 3 cm2) were defined on the left lower leg and treated, from cranial to caudal, with: (1) microneedling (MyM Dermapen; Bomtech Electronics Co., LTD, Seoul, South Korea; depth: 0.5 mm, one pass) (Figure 1A), (2) IM-0.05%-gel (Figure 1B), (3) microneedling and consecutive application of IM-0.05%-gel (Figure 1C), and (4) IM-0.05%-gel and consecutive microneedling (Figure 1D). The next day, only minimal pinpoint bleeding was apparent after microneedling alone (Figure 1A) and a very discrete inflammatory reaction was observed in the field treated with IM-0.05%-gel alone (Figure 1B). In comparison, both combination therapies resulted in increased inflammation with readily apparent erythema and formation of small vesicles (Figure 1C, D), with microneedling following application of IM-gel inducing the most intense inflammatory reaction of the 4 test fields. All inflammatory reactions healed within 2 weeks with a good cosmetic outcome and, significantly, a partial response for the combination treatments as compared to no response for the treatment with either microneedling or IM-gel alone. The patient did not report on any systemic side effects.
These findings support earlier reports describing an increase in drug efficacy in the treatment of AK after pretreatment with MADD. An increase in efficacy potentially widens the indication spectrum of IM to the treatment of thicker lesions or lesions in areas (e.g., extremities) that may show recalcitrance to conventional field therapy. Yet, it must be noted that IM is only approved for topical use and that up to date no safety data are available regarding a potential needling-induced systemic absorption of IM. In conclusion, these results indicate that IM can effectively be combined with microneedling and pave the way for expanded studies to determine the extent of enhancement of the efficacy and address safety of MADD-IM in the management of actinic field cancerization.

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