Topical doxycycline foam 4% for prophylactic management of epidermal growth factor receptor inhibitor skin toxicity: an exploratory phase 2, randomized, double-blind clinical study.

PURPOSE: Acneiform rash, a common toxicity of epidermal growth factor receptor inhibitors (EGFRIs), can cause patient discomfort, warranting changes in treatment. This study investigated the safety, tolerability, and efficacy of a novel doxycycline foam, FDX104 4%, for managing EGFRI-related skin toxicity. METHODS: This was an exploratory phase 2, randomized, double-blind, placebo-controlled study. Subjects had metastatic colorectal cancer and were being treated with either cetuximab or panitumumab plus chemotherapy. Treatment (twice-daily topical FDX104 4% on one side of the face and vehicle foam on the other for 5 weeks) was initiated 7 ± 3 days prior to EGFRI therapy. Rash severity, safety, and tolerability were evaluated at 2 and 4 weeks after EGFRI start. RESULTS: The mean maximal rash grade was lower with FDX104 4% vs vehicle, and fewer subjects developed moderate-to-severe (grades 2-3) rash. On the Global Severity Score scale, a statistically significant difference favored FDX104 4% over vehicle (P = .047). Adverse events (AEs) (n = 68) occurred in 20 subjects; most were mild or moderate. The most common AEs were oral mucositis, nausea, and vomiting, common to chemotherapy and EGFRI treatment. Study-drug-related AEs were experienced by five subjects and consisted of mild, local skin reactions. No study-drug-related systemic side effects were reported. CONCLUSION: Twice-daily, topical administration of FDX104 4% as an adjunct to either cetuximab or panitumumab was safe and well tolerated, and appeared to prevent the onset of rash, especially severe rash. CLINICALTRIALS. GOV IDENTIFIER: Trial Registration NCT02239731.

A Phase II, Randomized, Double-Blind Clinical Study Evaluating the Safety, Tolerability, and Efficacy of a Topical Minocycline Foam, FMX103, for the Treatment of Facial Papulopustular Rosacea.

OBJECTIVE: Our objective was to demonstrate the safety, tolerability, and efficacy of a minocycline foam, FMX103, in the treatment of moderate-to-severe facial papulopustular rosacea. METHODS: This was a phase II, randomized, double-blind, multicenter study. Healthy subjects aged ≥ 18 years with moderate-to-severe rosacea that had been diagnosed ≥ 6 months previously and with ≥ 12 inflammatory facial lesions were randomized (1:1:1) to receive once-daily 1.5% FMX103, 3% FMX103, or vehicle for 12 weeks. The primary endpoint was the absolute change in inflammatory lesion count at week 12. Other assessments included grade 2 or higher Investigator's Global Assessment (IGA) improvement, IGA "clear" or "almost clear" (IGA 0/1), clinical erythema, and safety/tolerability. Safety and efficacy were evaluated at weeks 2, 4, 8, and 12, with a safety follow-up at week 16. RESULTS: A total of 232 subjects were randomized; 213 completed the study. At week 12, inflammatory lesion count reduction was significantly greater for the 1.5 and 3% FMX103 doses than for vehicle (21.1 and 19.1 vs. 7.8, respectively; both p < 0.001). Both doses were significantly better than vehicle for achieving grade 2 or higher IGA improvement and assessment of "clear" or "almost clear." Both doses appeared generally safe and well tolerated. In total, 11 (4.7%) subjects reported treatment-related treatment-emergent adverse events (TEAEs); all but one (eye discharge) were dermal related, and all resolved by study end. No treatment-related systemic TEAEs were reported. Four subjects discontinued the study because of TEAEs (3% FMX103, n = 3; vehicle, n = 1). CONCLUSION: Topical minocycline foam, FMX103, appeared to be an effective, safe, and well tolerated treatment for moderate-to-severe papulopustular rosacea. These results support further investigation in larger clinical trials. CLINICALTRIALS. GOV IDENTIFIER: NCT02601963.

Topical Minocycline Foam for the Treatment of Impetigo in Children: Results of a Randomized, Double-Blind, Phase 2 Study.

BACKGROUND: Currently available treatment options for impetigo are limited by either systemic side effects (for oral therapy) or lack of ease of use (for topical ointment). A novel foam formulation of minocycline for topical use may improve convenience and treatment utilization for pediatric patients with impetigo. OBJECTIVE: To evaluate the safety and efficacy of topically applied minocycline foam (FMX-102 1% and 4%) in the treatment of impetigo and to determine the optimal therapeutic active ingredient concentration. METHODS: In this randomized, parallel-group, double-blind, comparative clinical trial, 32 subjects aged ≥2 years with a clinical diagnosis of pure impetigo, impetigo contagiosa, or uncomplicated blistering impetigo were randomized to treatment with FMX-102 1% or 4%, twice daily for 7 days. Subjects were followed for up to 7 days post-treatment. RESULTS: Clinical cure, defined as ≥80% cured lesions (fully recovered lesions, visually determined by investigators), was achieved by 57.1% and 50.0% of FMX-102 1% and 4% subjects, respectively, at the end of treatment (visit 3). Clinical success, defined as the absence of lesions, or the drying or improvement of treated lesions (decrease in size of affected area, lesion number, or both), was demonstrated in 81.3% and 78.6% of FMX-102 1% and 4% subjects, respectively, following 3 days of treatment (visit 2), in 92.3% and 100% of the respective subjects at the end of treatment, and in 100% in both groups at follow-up (visit 4). Bacteriologic success rates at the end of treatment, defined as complete pathogen eradication, were 85% and 74% in the FMX-102 1% and 4% groups, respectively. The bacteriologic success rate for MRSA infections was 100% (11/11), with no recurrences. Both FMX-102 1% and 4% were considered well tolerated and safe. CONCLUSION: Topical minocycline foam may be a safe and effective new treatment option for impetigo in children, including those with MRSA.

J Drugs Dermatol. 2016;15(10):1238-1243.

In vivo/ex vivo targeting of Langerhans cells after topical application of the immune response modifier TMX-202: confocal Raman microscopy and histology analysis.

The increased ability of TMX-202 (derivative of imiquimod) to penetrate the intact stratum corneum (SC) and the follicular orifices of porcine ear skin was shown ex vivo using confocal Raman microscopy and laser scanning microscopy. Moreover, to assess whether TMX-202 is able to reach the immune cells, Langerhans cells extracted from pretreated human skin were investigated ex vivo using confocal Raman microscopy combined with multivariate statistical methods. Tracking the Raman peak of dimethyl sulfoxide centered at 690 cm(−1), the absorption of TMX-202 containing formulation by Langerhans cells was shown. To answer the question whether the TMX-202 active ingredient is able to reach Langerhans cells, the attraction of immune cells to TMX-202 containing formulation treated skin was measured in the in vivo rodent model Mastomys coucha. The results show that TMX-202 active ingredient is able to reach Langerhans cells after penetrating through the intact skin and subsequently attract immune cells. Both the intercellular/transcellular as well as the follicular pathways allow the penetration through the intact barrier of the SC.

Emollient foam in topical drug delivery.

Foams offer an innovative and more convenient means of topical drug delivery. The successful introduction of hydroalcoholic foams paved the way for the development of a new generation of foam products that provide skin barrier build-up and hydration. Such foams, designated as emollient foams consist of oil-in-water or water-in-oil emulsions with necessary excipients, such as non-ionic surfactants, gelling agents and foam adjuvants. Emollient foams can carry a broad variety of topical drugs, including water-soluble, oil-soluble and suspended active agents. This paper reviews emollient foam compositions and their physicochemical properties. It further accounts for the usability and functional advantages of emollient foam as a vehicle of topical drugs, including: i) improved usability, which affects treatment, compliance and, consequently, improves therapeutic results; ii) safety; iii) controllable drug delivery; iv) skin barrier build-up and hydration; and v) enhanced clinical efficacy.

The toxicity of behenyl alcohol. I. Genotoxicity and subchronic toxicity in rats and dogs.

The genotoxic potential of behenyl alcohol, a saturated long-chain (C22:0) fatty alcohol, was examined in the Ames Salmonella typhimurium reverse mutation assay, the gene mutation, and chromosome aberrations assays in Chinese hamster V79 cells, and the micronucleus assay in NMRI mice. Behenyl alcohol did not increase the number of revertants per plate compared to controls in the S. typhimurium assay, with or without metabolic activation. No significant increases in the number of mutant colonies or in structural chromosome aberrations were observed in Chinese hamster V79 cells. In addition, behenyl alcohol did not increase the frequency of bone marrow polychromatic erythrocyte (PCE) micronuclei in mice in vivo. In two subchronic toxicity studies, CD rats and beagle dogs were administered behenyl alcohol by oral gavage for at least 26 weeks at doses of 0, 10, 100, or 1000 mg behenyl alcohol/kg body weight/day for rats and 0, 20, 200, or 2000 mg behenyl alcohol/kg body weight/day for dogs. Adverse effects were not observed following gross and histopathological evaluations of dosed rats. Compound-related effects in dogs were limited to observations of pale feces, indicative of unabsorbed behenyl alcohol, at doses of 2000 mg/kg body weight/day. There were no histopathological changes observed in dogs dosed with behenyl alcohol. The no-observed-adverse-effect-level (NOAEL) for behenyl alcohol was 1000 mg/kg body weight/day for rats, and 2000 mg/kg body weight/day for dogs, the highest doses used in these studies.

The toxicity of behenyl alcohol. II. Reproduction studies in rats and rabbits.

Behenyl alcohol is a saturated 22-carbon, long-chain aliphatic alcohol, which has potential for use in foods as an oil-structuring and -solidifying agent in fats. Previously completed studies with behenyl alcohol indicated an absence of mutagenic or genotoxic potential. In addition, subchronic toxicity studies in rats and dogs reported no adverse effects following gross and histopathological examinations. Compound-related effects were limited to the observation of pale feces in dogs treated with high doses of behenyl alcohol, and were attributable to unabsorbed behenyl alcohol. The reproductive effects of behenyl alcohol were investigated in a fertility and reproduction study, and an embryonic development study in rats and rabbits, respectively. No evidence of maternal or fetal toxicity was observed in either study. Behenyl alcohol demonstrated no effects on the fertility or reproduction of rats dosed up to 1000 mg/kg body weight. Similarly, behenyl alcohol had no reproductive effects on rabbits treated with doses up to 2000 mg/kg body weight. The observation of pale feces was the only compound-related effect reported, limited to rabbits treated with 2000 mg behenyl alcohol/kg body weight. Based on these findings, there is no evidence to suggest that behenyl alcohol is teratogenic or embryotoxic.

Percutaneous penetration and skin metabolism of ethylsalicylate-containing agent, TU-2100: in-vitro and in-vivo evaluation in guinea pigs.

The aim of this study was to investigate the percutaneous penetration and dermal metabolism of a new potential anti-acne prodrug--TU-2100 [bis(o-carboxyphenyl ethyl ester)nonanedioate] in guinea pigs. The fluxes of this agent through excised skin after applications of TU-2100 gels at 3 and 10% concentrations were similar. However, after 24 h from the time of drug application, the total amounts of permeated TU-2100 into the skin compartment and through the skin into the receiver were 271.7 (+/-30.7 S.E.) microg/cm(2) from the 3% gel and 779.4.0 (+/-98.5 S.E.) microg/cm(2) from the 10% gel, demonstrating a relatively high skin accumulation. Higher degradation of TU-2100 to ethylsalicylate occurred after application of drug at 10% concentration than after the application of 3% gel. In contrast, the fraction of permeated drug metabolized was twofold higher after the 3% gel application than after the 10% gel (F(m)=20 vs. 10.5 mole %). Since F(m) is reversibly related to the total permeating drug, the obtained values actually reflect the significant difference in TU-2100 permeation from the 3% (271.7 microg) and the 10% (779.4 microg) gels. An in vivo--in vitro comparison revealed similar drug accumulations in the skin after application of both 3 and 10% gels, however, skin metabolism was found to be significantly higher in vivo than in vitro.