Journal of Dermatological Treatment
ISSN: 0954-6634 (Print) 1471-1753 (Online) Journal homepage: http://www.tandfonline.com/loi/ijdt20
Safety, tolerability and pharmacokinetics of a novel phosphodiesterase inhibitor, E6005 ointment, in healthy volunteers and in patients with atopic dermatitis Fuminori Ohba, Maiko Nomoto, Seiichiro Hojo & Hideto Akama To cite this article: Fuminori Ohba, Maiko Nomoto, Seiichiro Hojo & Hideto Akama (2016) Safety, tolerability and pharmacokinetics of a novel phosphodiesterase inhibitor, E6005 ointment, in healthy volunteers and in patients with atopic dermatitis, Journal of Dermatological Treatment, 27:3, 241-246, DOI: 10.3109/09546634.2015.1093587 To link to this article: http://dx.doi.org/10.3109/09546634.2015.1093587
Published online: 18 Nov 2015.
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Date: 28 September 2017, At: 05:38
http://tandfonline.com/ijdt ISSN: 0954-6634 (print), 1471-1753 (electronic) J Dermatolog Treat, 2016; 27(3): 241–246 ! 2015 Taylor & Francis. DOI: 10.3109/09546634.2015.1093587
ORIGINAL ARTICLE
Safety, tolerability and pharmacokinetics of a novel phosphodiesterase inhibitor, E6005 ointment, in healthy volunteers and in patients with atopic dermatitis Fuminori Ohba, Maiko Nomoto, Seiichiro Hojo and Hideto Akama
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Eisai Product Creation Systems, Eisai Co., Ltd., Tokyo, Japan
Abstract
Keywords
Objectives: The purpose of the present studies was to assess the safety, tolerability and pharmacokinetics of topical application of a novel phosphodiesterase inhibitor, E6005, in healthy volunteers and in patients with atopic dermatitis (AD). Methods: In two randomized, investigator-blind, vehicle-controlled studies, we evaluated the topical application of E6005 ointment at concentrations ranging from 0.01% to 0.2% in healthy volunteers (Study 001) and in patients with AD (Study 101). Results: Thirty-six subjects were enrolled in Study 001 and 40 in Study 101. Neither skin irritation nor photosensitization was observed with application of E6005 in Study 001. Four subjects receiving E6005 in Study 001 experienced a treatment-emergent adverse event (application site edema, increased alanine aminotransferase or erythema); three of these subjects discontinued the study. Two subjects receiving E6005 in Study 101 experienced an adverse event (gout or enterocolitis); one discontinued the study. Plasma concentrations of E6005 were below the limit of quantification (1 ng/ml) in both studies. Conclusion: E6005 ointment exhibited acceptable safety and tolerability. Topical application of E6005 ointment resulted in very low systemic exposure to E6005 in healthy volunteers and in patients with AD.
Atopic eczema, clinical trial, patch test, phosphodiesterase-4 inhibitor, photopatch test, topical treatment
Introduction Atopic dermatitis (AD) is a chronic, inflammatory, pruritic skin disease that affects large numbers of children, adults and their families in industrialized countries (1). The pathogenesis of AD is attributed to complex interactions between the environment and host susceptibility genes, which alter skin barrier function and the immune system (2). It has been known since the 1980s that leukocytes from patients with AD display reduced cyclic adenosine monophosphate (cAMP) responses to stimulation (3) and elevated phosphodiesterase (PDE) activity, leading to leukocyte hyperactivity and inflammation (4–6). Several PDE type 4 (PDE4) inhibitors have been developed to treat chronic inflammatory disorders. For example, roflumilast is approved as an oral add-on therapy for chronic obstructive pulmonary disease (7), and apremilast has been developed to treat psoriasis (8). However, the clinical utility of PDE4 inhibitors has so far been compromised by the occurrence of mechanismassociated adverse reactions, including nausea, vomiting, headache and weight loss, which often limit the maximum tolerated dose (9,10). However, a topically active PDE4 inhibitor with low transdermal bioavailability could be clinically useful.
Correspondence: Fuminori Ohba, Eisai Product Creation Systems, Eisai Co., Ltd., 4-6-10, Koishikawa, Bunkyo-ku, Tokyo 112-8088, Japan. Tel: +81 3 3817 5199. Fax: +81 3 3811 7339. E-mail: [email protected]
History Received 11 June 2015 Accepted 5 September 2015 Published online 22 October 2015
To minimize systemic exposure, E6005 (molecular weight: 472.49) was developed as a novel PDE4 inhibitor for topical use (11,12). E6005 has shown potent and selective inhibition of PDE4, and suppresses the production of proinflammatory cytokines by human lymphocytes and monocytes (11). In mouse models, E6005 ointment application has shown an immediate antipruritic effect, as well as an anti-inflammatory effect, with reduced expression of cytokines and adhesion molecules (11). We conducted two randomized, investigator-blind, vehicle-controlled, multiple ascending dose studies to evaluate the safety and pharmacokinetics of E6005 ointment in healthy volunteers and in patients with AD.
Methods E6005 ointment in a base of white petrolatum (Eisai Co., Ltd., Tokyo, Japan) was evaluated with a vehicle control in two randomized studies conducted from 2009 to 2010. The study objectives were as follows: E6005-J081-001: The primary objective was to assess the safety and pharmacokinetics of E6005 applied repeatedly to the skin of healthy Japanese men at concentrations of 0.01%, 0.03%, 0.1% or 0.2%, compared with vehicle. This study was conducted at the Sekino Clinical Pharmacology Clinic, Tokyo, Japan, in 2009. E6005-J081-101 (ClinicalTrials.gov Identifier: NCT01179880, JapicCTI-101266): The primary objective was to assess the safety
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and pharmacokinetics of topical application of E6005 ointment (0.01%, 0.03%, 0.1% or 0.2%) compared with vehicle in Japanese men with AD. This study was conducted at the Kyushu Clinical Pharmacology Research Clinic, Fukuoka, Japan, in 2010. Both studies were performed in full compliance with the International Conference on Harmonisation, all applicable Good Clinical Practice guidelines and local regulations in Japan, and were approved by the institutional investigational review boards. All the patients provided written informed consent.
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Study subjects E6005-J081-001: Eligible participants were healthy Japanese adult male volunteers aged 20–45 years with a body mass index between 18.5 and 25.0 kg/m2. Subjects were excluded if they had any skin disease or history of allergy that could jeopardize study results. E6005-J081-101: Japanese patients eligible for Study 101 were men aged 20–65 years with a confirmed clinical diagnosis of mild to severe AD, according to the Japanese Dermatological Association’s ‘‘Guidelines for Management of Atopic Dermatitis’’ (13). Patients needed to have evaluable typical eczema on the posterior trunk (targeted eczema lesions) to explore the efficacy of topical application of E6005 ointment. Patients were excluded if they had additional skin diseases that could jeopardize study results. Patients were required to stop all the topical AD therapies except for white petrolatum (such as topical corticosteroids and calcineurin inhibitors) at least 1 week prior to baseline evaluation, and to discontinue any systemic therapy (antihistamines, systemic corticosteroids, cyclosporine and tacrolimus), phototherapy and photochemotherapy at least 2 weeks prior to baseline evaluation. Study design In Study 001, participants were divided into four cohorts of nine subjects each, according to the concentration of E6005 ointment applied (0.01%, 0.03%, 0.1% or 0.2%). Seven subjects in each cohort were randomly selected to receive E6005 ointment application, while two received vehicle application. Each cohort participated in three testing periods (Figure 1a). In Period 1, 30 mg of the investigational drugs (no treatment; white petrolatum; vehicle; 0.01%, 0.03%, 0.1% and 0.2% E6005) were individually placed in two sets of Finn ChambersÕ (Epitest Ltd Oy, Tuusula, Finland) for patch and photopatch testing. The Finn ChambersÕ were applied to the outer surface of the upper arms on day 1. In Period 2, a simple application of the investigational drug was applied to the posterior trunk at dosages of 1 g in the morning on day 9, 2 g in the morning on day 11 and 5 g in the morning on day 13. In Period 3, on days 15–19, repeated 5 g doses were applied in the morning and at night. The type of ointment applied (E6005 or vehicle) was masked to assessment investigators and to subjects. When no safety concerns arose within a cohort, the next cohort was started with a higher E6005 concentration. Study 101 consisted of four cohorts of 10 patients each. Within each cohort, eight patients were randomly selected to receive application of 5 g of E6005 ointment and two received 5 g of vehicle ointment once on day 1, twice daily on days 2 through 9 and once on day 10. A different concentration of E6005 (0.01%, 0.03%, 0.1% or 0.2%) was applied in each cohort. The ointment was applied first to the targeted eczema lesion on the back, next to other regions of the trunk and finally to the lower limbs if sufficient ointment remained, while avoiding the head, neck and upper limbs. The type of ointment applied (E6005 or vehicle) was masked to assessment investigators and to patients. When no safety concerns arose within a cohort, the next cohort was started with a higher concentration of E6005.
J Dermatolog Treat, 2016; 27(3): 241–246
Assessments In the patch test (skin irritation test), the investigational drugs were applied to the skin for 48 h. Skin reactions were assessed 30 min and 24, 72 and 120 h after removing the Finn ChamberÕ , according to the criteria of the International Contact Dermatitis Research Group (14) and Japanese criteria (15). In the photopatch test (photosensitivity test), the investigational drugs were applied for 24 h. The skin was then exposed to long-wavelength irradiation (UVA, 6 J/cm2). The presence or absence of light urticaria was assessed 30 min after optical irradiation, and the site was then covered with a new empty Finn ChamberÕ for 1 day. Skin reactions were assessed 24, 48, 96 and 144 h after optical irradiation, according to the criteria of the International Contact Dermatitis Research Group (16) and Japanese criteria (15). All the skin reactions were assessed by a physician who was kept blind to the preparation sequence. The assessor did not apply or remove the preparations during the study and was never told the preparation sequence. A photograph of the application site was taken before application and at the time of assessment. The safety profile was assessed with treatment-emergent adverse event reporting, based on the Common Terminology Criteria for Adverse Events (National Cancer Institute, Bethesda, MD, version 4.02), clinical laboratory testing, electrocardiogram recording, vital signs and ophthalmological findings. Measurement of plasma concentrations of E6005 and its metabolite In Study 001, blood samples were collected for assessment of pharmacokinetics before initial treatment, before dosing on days 8, 9, 11, 13, 15 and 19, and at 1-, 2-, 4- and 8-h post-dose on days 15 and 19. In Study 101, blood samples were collected pre-dose on days 1, 2, 5, 10, 11, 12 and 13, and 1-, 2-, 4- and 8-h post-dose on days 1, 5 and 10. Plasma concentrations of E6005 and its major metabolite (the methyl ester hydrolysis product) were quantified with a validated liquid chromatography-tandem mass spectrometry method with a lower limit of quantification of51 ng/ml (11). Statistical analysis Randomization schedules were generated by the SAS RANUNI procedure. All the analyses were performed by Eisai Co., Ltd. using SASÕ for Windows (SAS Institute, Cary, NC, Version 8.2 or later). The full analysis set population was used for all the analyses. Data were summarized descriptively according to treatment. For continuous variables, descriptive statistics are generally presented where applicable (including number of subjects [N], percentage of subjects [%], arithmetic mean [mean] and standard deviation [SD]).
Results Demographics and baseline characteristics In Study 001, 36 healthy male subjects were randomized: 28 to active treatment and 8 to vehicle. Thirty-three of these completed the study and three did not (two because of adverse events and one because of subject choice) (Figure 1a). Demographics and baseline characteristics were generally similar among all the treatment groups (Table 1). In Study 101, 40 male patients were randomized: 32 to active treatment and 8 to vehicle. Thirty-eight of these completed the study. One patient in the 0.03% E6005 ointment treatment group withdrew because of an adverse event; another in the vehicle treatment group withdrew because of AD progression (Figure 1b).
Safety and pharmacokinetic profile of E6005
DOI: 10.3109/09546634.2015.1093587
Period 1
Period 2
Period 3
Days 1–8
Days 9–14
Days 15–22
Patch test and Photopatch test
1 g on day 9, 2 g on day 11, 5 g on day 13
5 g twice daily on days 15–19
Cohort 1 (9 subjects)
0.01% E6005 (7 active, 2 vehicle)
0.01% E6005 (7 active, 2 vehicle)
Cohort 2 (9 subjects)
0.03% E6005 (7 active, 2 vehicle)
0.03% E6005 (7 active, 2 vehicle)
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36 subjects randomized Cohort 3 (9 subjects)
0.1% E6005 (7 active, 2 vehicle)
0.1% E6005 (7 active, 2 vehicle)
1 patient in the active group was withdrawn on day 13 because of subject choice. 1 patient in the vehicle group was withdrawn on day 16 because of an adverse event.
Cohort 4 (9 subjects)
0.2% E6005 (7 active, 2 vehicle)
0.2% E6005 (7 active, 2 vehicle)
1 patient in the active group was withdrawn on day 16 because of an adverse event.
5 g once daily on days 1 and 10, 5 g twice daily on days 2–9
Cohort 1 0.01% E6005 (8 active, 2 vehicle)
Cohort 2 0.03% E6005 (8 active, 2 vehicle)
1 patient in the active group was withdrawn on day 6 because of an adverse event. 1 patient in the vehicle group was withdrawn on day 6 because of progression of atopic dermatitis.
40 subjects randomized Cohort 3 0.1% E6005 (8 active, 2 vehicle)
Cohort 4 0.2% E6005 (8 active, 2 vehicle)
Figure 1. Subject disposition. (a) Design and subject allocation schema for Study 001. (b) Design and subject allocation schema for Study 101.
Demographics and baseline characteristics were generally similar among all the treatment groups (Table 1). Skin irritation and photosensitivity In the skin irritation test in Study 001, four subjects had a positive reaction 30 min after removal of the Finn ChamberÕ (Table 2).
One subject, who experienced application site edema without erythema at the site of the ‘‘no application’’ chamber as a treatment-emergent adverse event, improved without treatment and the reaction was considered not related to the study drug. Three subjects experienced faint application site erythema, one at the site of no treatment, one at the white petrolatum site and one at the 0.2% E6005 site. These were not classified as adverse
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Table 1. Subject demographics and baseline characteristics. E6005
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Characteristics Study 001 Age (years), mean ± SD Height (cm), mean ± SD Weight (kg), mean ± SD BMI (kg/m2), mean ± SD TEWLy (g/m2h), mean ± SD Study 101 Age (years), mean ± SD Height (cm), mean ± SD Weight (kg), mean ± SD BMI (kg/m2), mean ± SD TEWLa (g/m2h), mean ± SD Severity of AD, n Mild Moderate Severe Very severe Duration of AD (years), mean ± SD History of other allergy, n TEWL (g/m2h) at eczema, mean ± SD
Total (n ¼ 36)
Vehicle (n ¼ 8)
0.01% (n ¼ 7)
0.03% (n ¼ 7)
0.1% (n ¼ 7)
0.2% (n ¼ 7)
26.3 ± 4.2 174.69 ± 4.48 66.66 ± 5.24 21.84 ± 1.31 10.87 ± 5.12
25.8 ± 4.5 175.34 ± 4.26 68.83 ± 6.16 22.38 ± 1.57 12.23 ± 5.43
25.4 ± 2.4 172.93 ± 4.42 63.99 ± 3.13 21.40 ± 0.70 8.89 ± 1.56
24.7 ± 3.7 174.59 ± 2.90 65.63 ± 4.61 21.53 ± 1.26 10.31 ± 1.91
27.1 ± 3.7 177.36 ± 5.98 70.50 ± 6.13 22.41 ± 1.82 13.16 ± 9.70
28.7 ± 5.6 173.13 ± 4.11 64.06 ± 2.47 21.40 ± 0.65 9.56 ± 1.70
27.2 ± 7.3 172.20 ± 5.81 66.11 ± 8.96 22.30 ± 2.91 16.96 ± 6.57
27.3 ± 8.6 170.58 ± 8.04 66.53 ± 8.97 22.90 ± 3.11 16.11 ± 5.92
25.5 ± 6.8 170.84 ± 4.85 68.08 ± 7.47 23.39 ± 2.85 16.38 ± 6.06
24.5 ± 3.8 173.10 ± 5.77 62.95 ± 12.19 20.93 ± 3.39 24.23 ± 7.56
29.3 ± 7.5 175.05 ± 4.85 67.28 ± 7.44 21.95 ± 2.37 12.51 ± 3.79
29.4 ± 9.2 171.43 ± 5.20 65.74 ± 9.42 22.35 ± 2.89 15.59 ± 3.26
2 3 2 1 17.71 ± 9.69 2 23.19 ± 5.01
3 5 0 0 22.37 ± 6.02 1 40.64 ± 17.16
10 22 6 2 17.86 ± 8.71 6 29.39 ± 12.50
1 5 1 1 11.30 ± 8.61 1 30.15 ± 12.66
2 4 2 0 16.55 ± 7.34 1 28.81 ± 12.14
2 5 1 0 21.01 ± 8.66 1 24.18 ± 4.83
AD, atopic dermatitis; BMI, body mass index; SD, standard deviation; TEWL, transepidermal water loss. Measured on normal skin.
a
Table 2. Skin irritation test results (International Contact Dermatitis Research Group criteria). E6005 Interpretation Skin irritation test (patch test) No reaction Doubtful reaction (faint erythema only) Weak positive reaction (erythema, infiltration, possibly papules) Strong positive reaction (erythema, infiltration, papules, vesicles) Extreme positive reaction (intense erythema, infiltration, coalescing vesicles) Irritant reaction of a different type
No treatment (n ¼ 36)
White petrolatum (n ¼ 36)
Vehicle (n ¼ 36)
0.01% (n ¼ 36)
0.03% (n ¼ 36)
0.1% (n ¼ 36)
0.2% (n ¼ 36)
34 (94.4%) 1 (2.8%)
35 (97.2%) 1 (2.8%)
36 (100%) 0
36 (100%) 0
36 (100%) 0
36 (100%) 0
35 (97.2%) 1 (2.8%)
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
1 (2.8%)
events, because assessment investigators considered the erythema in these cases to be related to physical contact with the chamber. Photosensitivity testing was negative in all the participants. Safety and tolerability In Study 001, 4 of 28 subjects (14.3%) in the E6005 ointment treatment group and 1 of 8 (12.5%) in the vehicle treatment group had at least one treatment-emergent adverse event (Table 3). One subject, who experienced application site edema in the patch test/ photopatch test, is described earlier. Two subjects in the 0.1% E6005 ointment group experienced increased alanine aminotransferase. One discontinued the study on day 13 because of subject choice and improved without treatment. This elevation was considered to be possibly related to the study drug. The second participant continued the study, improved without treatment and the elevation was considered not related to the study drug. One subject in the 0.2% E6005 ointment treatment group and one
in the vehicle treatment group in Cohort 3 experienced erythema, which occurred in the application area and in a non-application area. Both participants discontinued the study on Day 16, improved without treatment and the reactions were considered not related to the study drug. Deaths and other serious or severe adverse events (Grade 3 or higher) were not observed. Laboratory parameters, vital signs, electrocardiogram parameters and ophthalmological examination findings did not change clinically. In Study 101, 2 of 32 patients (6.3%) in the E6005 ointment treatment group and 1 of 8 (12.5%) in the vehicle treatment group had at least one treatment-emergent adverse event (Table 3). One patient in the 0.03% E6005 ointment treatment group had gout, which occurred in a non-drug application area and improved even after application of the drug. A patient in the 0.2% E6005 ointment treatment group had enterocolitis, which improved despite continuation of the study drug; this patient also had a past history of lower abdominal pain during constipation. Another patient in the vehicle treatment group in Cohort 2 experienced
Safety and pharmacokinetic profile of E6005
0.2% (n ¼ 8)
1 (12.5%)
1 (12.5%)
0
0
0
0
0 0
0.1% (n ¼ 8)
0
0
0
0
0
0
0 0
Pharmacokinetic profile
0 0 1 (12.5%) 0
In both studies, plasma concentrations of E6005 were below the lower limit of quantification (1 ng/ml) at all the sampling points in all the subjects, so it was not possible to obtain any meaningful pharmacokinetic data (Table 4). In Study 001, plasma concentrations of the metabolite M11 were also below the lower limit of quantification (1 ng/ml). In Study 101, the metabolite M11 was detected in the plasma at levels just above the lower limit of quantification (1 ng/ml) and53 ng/ml in 3 of 36 patients (8.3%; in two receiving 0.1% E6005 ointment treatment and in one receiving 0.2% E6005 ointment treatment).
0 0
1 (12.5%) 0 0
0 0
0 1 (14.3%)
Discussion
Medical Dictionary for Regulatory Activities, version 17.1.
a
0 0 0 1 (12.5%)
0 0
0 0
0
0
0
0 0 0 0
0
2 (28.6%)
0
0
0 0 1 (12.5%) 0 0
0
0
0
0 0 0 1 (14.3%) 0
0
0
0
0 0 0 0
0
0
0
0
1 (12.5%) 0 1 (12.5%) 1 (14.3%) 2 (28.6%) 0 1 (14.3%) 1 (12.5%)
Any adverse event Gastrointestinal disorders Enterocolitis General disorders and administration site conditions Application site edema Infections and infestations Kaposi’s varicelliform eruption Investigations Alanine aminotransferase increased Metabolism and nutrition disorders Gout Skin and subcutaneous tissue disorders Dermatitis, atopic Erythema
0.03% (n ¼ 8) 0.01% (n ¼ 8) Vehicle (n ¼ 8) 0.1% (n ¼ 7) 0.03% (n ¼ 7) 0.01% (n ¼ 7) Vehicle (n ¼ 8) MedDRA system organ class and preferred terma
Table 3. Treatment-emergent adverse events.
245
aggravated AD and Kaposi’s varicelliform eruption. None of these adverse events were considered to be related to the study drug. Deaths and other serious or severe adverse events (Grade 3 or higher) were not observed. Laboratory parameters, vital signs, electrocardiogram parameters and ophthalmological examinations did not change clinically.
E6005 E6005
Healthy volunteers (Study 001)
0.2% (n ¼ 7)
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Patients with atopic dermatitis (Study 101)
DOI: 10.3109/09546634.2015.1093587
Neither skin irritation nor photosensitization was observed in subjects treated with E6005 ointment or vehicle ointment, according to Japanese and International Contact Dermatitis Research Group criteria. In addition, there was no specific adverse reaction reported at any E6005 concentration up to 0.2% in this study. These results, including the assessments according to Japanese criteria (15), indicate no safety concerns for skin application of E6005 ointment or vehicle, including skin irritation, phototoxicity or light urticaria. Tacrolimus ointment is widely used in treating AD. The most common adverse effects of tacrolimus ointment are a burning sensation and pruritus at the site of application, occurring during the first few days of treatment (17). In our studies of healthy volunteers and patients with AD, no application site reaction, including burning sensation and pruritus, occurred with use of E6005 ointment. Although our studies did not compare topical E6005 with tacrolimus, our results indicate that E6005 ointment may have a safer profile. In all the healthy volunteers, plasma concentrations of E6005 and its metabolite M11 were below the limit of quantification at all the sampling points during the 5-day repeated application of E6005 ointment. The present findings are consistent with the results obtained when testing healthy skin in rats (11,12). Although E6005 was not detected in the plasma of any patient with AD in the present study, the metabolite M11 was detected in the plasma of three. These results suggest that the stratum corneum is a major barrier to E6005 absorption through the skin in humans (as in rats) and that a small quantity of E6005 is absorbed through eczematous lesions in humans. Furthermore, an in vitro metabolism study using liver microsomes from humans and other animals showed rapid metabolism of E6005 to M11. Together these results suggest low absorption and rapid elimination of E6005 from the systemic circulation in humans. Nausea, vomiting, headache and weight loss, which are the commonly reported adverse reactions associated with other PDE4 inhibitors (9,10), were not observed in the present studies. PDE4 inhibitors are thought to produce a pharmacological response analogous to that of presynaptic a2-adrenoceptor inhibitors by elevating intracellular levels of cAMP in noradrenergic neurons (18). One way to evaluate the emetic potential of this class of drugs is to assess the anaesthesia-reversing effect of PDE4 inhibitors in rats, which do not have a vomiting reflex (19). In a study using this model of emesis, the reversal of anaesthesia with systemic E6005 administration was less potent than that with cilomilast administration (11). Additionally, as discussed earlier,
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Table 4. Number of subjects with plasma concentrations of E6005 or M11 above the lower limit of quantification. Healthy volunteers (Study 001)
Patients with atopic dermatitis (Study 101)
E6005
E6005
Vehicle (n ¼ 8)
0.01% (n ¼ 7)
0.03% (n ¼ 7)
0.1% (n ¼ 7)
0.2% (n ¼ 7)
Vehicle (n ¼ 8)
0.01% (n ¼ 8)
0.03% (n ¼ 8)
0.1% (n ¼ 8)
0.2% (n ¼ 8)
0 0
0 0
0 0
0 0
0 0
0 0
0 0
0 0
0 2 (25.0%)
0 1 (12.5%)
E6005 M11
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The lower limit of quantification was 1.00 ng/ml.
absorption of E6005 is restricted by the stratum corneum, and absorbed E6005 is rapidly metabolized to M11. Furthermore, the metabolite M11 is 100 times weaker than E6005 in suppressing cytokine production by human monocytes, possibly because of its lower cell membrane permeability (11,12). Thus, the adverse reactions commonly reported with the use of other PDE4 inhibitors are expected to be less common with topical E6005 use. This could provide a new treatment option for AD that avoids safety concerns associated with PDE4 inhibitors, while maintaining similar effectiveness (12).
Conclusions
5.
6. 7. 8.
In conclusion, our preliminary data indicate that E6005 ointment is safe and well tolerated in healthy volunteers and in patients with AD, although the results should be interpreted with caution because of the small number of subjects included. Further studies are necessary to evaluate the safety of E6005 ointment applied to larger areas throughout the body for longer periods.
10.
Acknowledgements
11.
We would like to thank the investigators and their teams at the Sekino Clinical Pharmacology Clinic and the Kyushu Clinical Pharmacology Research Clinic. Gratitude is expressed to Professor Akiyoshi Fukamizu (University of Tsukuba) for his critical reading of the article.
12.
9.
Declaration of interest F.O., M.N., S.H. and H.A. are employed by Eisai Co., Ltd., which holds patents on E6005 (US7939540, EP1992622, JP4778550). Eisai Co, Ltd. manufactured the E6005 ointment, sponsored the present studies, was involved in the design and execution of the studies; in the collection, analysis and interpretation of data; and in the preparation, review and approval of the article prior to submission.
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13. 14. 15. 16. 17. 18.
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AMP-agonist hyporesponsiveness. J Allergy Clin Immunol. 1982; 70:452–7. Chan SC, Reifsnyder D, Beavo JA, Hanifin JM. Immunochemical characterization of the distinct monocyte cyclic AMP-phosphodiesterase from patients with atopic dermatitis. J Allergy Clin Immunol. 1993;91:1179–88. Hanifin JM, Chan SC. Monocyte phosphodiesterase abnormalities and dysregulation of lymphocyte function in atopic dermatitis. J Allergy Clin Immunol. 1995;105(Suppl):84S–8. Calverley PMA, Sanchez-Toril F, McIvor A, et al. Effect of 1-year treatment with roflumilast in severe chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2007;176:154–61. Papp KA, Kaufmann R, Thac¸hi D, et al. Efficacy and safety of apremilast in subjects with moderate to severe plaque psoriasis: results from a phase II, multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-comparison study. J Eur Acad Dermatol Venereol. 2013;27:e376–83. Galvalda´ A, Roberts RS. Phosphodiesterase-4 inhibitors: a review of current developments (2010–2012). Expert Opin Ther Patents. 2013; 23:997–1016. Page´s L, Gavalda´ A, Lehner MD. PDE4 inhibitors: a review of current developments (2005–2009). Expert Opin Ther Patents. 2009; 19:1501–19. Ishii N, Shirato M, Wakita H, et al. Anti-pruritic effect of the topical phosphodiesterase 4 inhibitor E6005 ameliorates skin lesions in a mouse atopic dermatitis model. J Pharmacol Exp Ther. 2013;346: 105–12. Furue M, Kitahara Y, Akama H, et al. Safety and efficacy of topical E6005, a phosphodiesterase 4 inhibitor, in Japanese adult patients with atopic dermatitis: results of a randomized, vehicle-controlled, multicenter clinical trial. J Dermatol. 2014;41:577–85. Saeki H, Furue M, Furukawa F, et al. Guidelines for management of atopic dermatitis. J Dermatol. 2009;36:563–77. Wahlberg JE, Lindberg M. Patch testing. In Frosch PJ, Menne T, Lepoittevin JP, eds. Contact Dermatitis. 4th ed. Berlin: Springer, 2006. p 366–90. Irie S, Tsukikawa H, Nabeshima T, et al. Skin tests of a novel nicotine patch, PHK-301p, in healthy male volunteers: phase I, placebo-controlled study. J Pharmacol Sci. 2006;102:72–6. Palmer RA, White IR. Photopatch testing. In Frosch PJ, Menne T, Lepoittevin JP, eds. Contact Dermatitis. 4th ed. Berlin: Springer, 2006 p 433–40. Nakagawa H. Comparison of the efficacy and safety of 0.1% tacrolimus ointment with topical corticosteroids in adult patients with atopic dermatitis. Clin Drug Invest. 2006;26:235–46. Robichaud A, Stamatiou PB, Jin SLC, et al. Deletion of phosphodiesterase 4D in mice shortens a2-adrenoceptor-mediated anesthesia, a behavioral correlate of emesis. J Clin Invest. 2002;110: 1045–52. Robichaud A, Tattersall FD, Choudhury I, et al. Emesis induced by inhibitors of type IV cyclic nucleotide phosphodiesterase (PDE IV) in the ferret. Neuropharmacology. 1999; 38:289–97.
ISSN: 0954-6634 (Print) 1471-1753 (Online) Journal homepage: http://www.tandfonline.com/loi/ijdt20
Safety, tolerability and pharmacokinetics of a novel phosphodiesterase inhibitor, E6005 ointment, in healthy volunteers and in patients with atopic dermatitis Fuminori Ohba, Maiko Nomoto, Seiichiro Hojo & Hideto Akama To cite this article: Fuminori Ohba, Maiko Nomoto, Seiichiro Hojo & Hideto Akama (2016) Safety, tolerability and pharmacokinetics of a novel phosphodiesterase inhibitor, E6005 ointment, in healthy volunteers and in patients with atopic dermatitis, Journal of Dermatological Treatment, 27:3, 241-246, DOI: 10.3109/09546634.2015.1093587 To link to this article: http://dx.doi.org/10.3109/09546634.2015.1093587
Published online: 18 Nov 2015.
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Date: 28 September 2017, At: 05:38
http://tandfonline.com/ijdt ISSN: 0954-6634 (print), 1471-1753 (electronic) J Dermatolog Treat, 2016; 27(3): 241–246 ! 2015 Taylor & Francis. DOI: 10.3109/09546634.2015.1093587
ORIGINAL ARTICLE
Safety, tolerability and pharmacokinetics of a novel phosphodiesterase inhibitor, E6005 ointment, in healthy volunteers and in patients with atopic dermatitis Fuminori Ohba, Maiko Nomoto, Seiichiro Hojo and Hideto Akama
Downloaded by [Australian Catholic University] at 05:38 28 September 2017
Eisai Product Creation Systems, Eisai Co., Ltd., Tokyo, Japan
Abstract
Keywords
Objectives: The purpose of the present studies was to assess the safety, tolerability and pharmacokinetics of topical application of a novel phosphodiesterase inhibitor, E6005, in healthy volunteers and in patients with atopic dermatitis (AD). Methods: In two randomized, investigator-blind, vehicle-controlled studies, we evaluated the topical application of E6005 ointment at concentrations ranging from 0.01% to 0.2% in healthy volunteers (Study 001) and in patients with AD (Study 101). Results: Thirty-six subjects were enrolled in Study 001 and 40 in Study 101. Neither skin irritation nor photosensitization was observed with application of E6005 in Study 001. Four subjects receiving E6005 in Study 001 experienced a treatment-emergent adverse event (application site edema, increased alanine aminotransferase or erythema); three of these subjects discontinued the study. Two subjects receiving E6005 in Study 101 experienced an adverse event (gout or enterocolitis); one discontinued the study. Plasma concentrations of E6005 were below the limit of quantification (1 ng/ml) in both studies. Conclusion: E6005 ointment exhibited acceptable safety and tolerability. Topical application of E6005 ointment resulted in very low systemic exposure to E6005 in healthy volunteers and in patients with AD.
Atopic eczema, clinical trial, patch test, phosphodiesterase-4 inhibitor, photopatch test, topical treatment
Introduction Atopic dermatitis (AD) is a chronic, inflammatory, pruritic skin disease that affects large numbers of children, adults and their families in industrialized countries (1). The pathogenesis of AD is attributed to complex interactions between the environment and host susceptibility genes, which alter skin barrier function and the immune system (2). It has been known since the 1980s that leukocytes from patients with AD display reduced cyclic adenosine monophosphate (cAMP) responses to stimulation (3) and elevated phosphodiesterase (PDE) activity, leading to leukocyte hyperactivity and inflammation (4–6). Several PDE type 4 (PDE4) inhibitors have been developed to treat chronic inflammatory disorders. For example, roflumilast is approved as an oral add-on therapy for chronic obstructive pulmonary disease (7), and apremilast has been developed to treat psoriasis (8). However, the clinical utility of PDE4 inhibitors has so far been compromised by the occurrence of mechanismassociated adverse reactions, including nausea, vomiting, headache and weight loss, which often limit the maximum tolerated dose (9,10). However, a topically active PDE4 inhibitor with low transdermal bioavailability could be clinically useful.
Correspondence: Fuminori Ohba, Eisai Product Creation Systems, Eisai Co., Ltd., 4-6-10, Koishikawa, Bunkyo-ku, Tokyo 112-8088, Japan. Tel: +81 3 3817 5199. Fax: +81 3 3811 7339. E-mail: [email protected]
History Received 11 June 2015 Accepted 5 September 2015 Published online 22 October 2015
To minimize systemic exposure, E6005 (molecular weight: 472.49) was developed as a novel PDE4 inhibitor for topical use (11,12). E6005 has shown potent and selective inhibition of PDE4, and suppresses the production of proinflammatory cytokines by human lymphocytes and monocytes (11). In mouse models, E6005 ointment application has shown an immediate antipruritic effect, as well as an anti-inflammatory effect, with reduced expression of cytokines and adhesion molecules (11). We conducted two randomized, investigator-blind, vehicle-controlled, multiple ascending dose studies to evaluate the safety and pharmacokinetics of E6005 ointment in healthy volunteers and in patients with AD.
Methods E6005 ointment in a base of white petrolatum (Eisai Co., Ltd., Tokyo, Japan) was evaluated with a vehicle control in two randomized studies conducted from 2009 to 2010. The study objectives were as follows: E6005-J081-001: The primary objective was to assess the safety and pharmacokinetics of E6005 applied repeatedly to the skin of healthy Japanese men at concentrations of 0.01%, 0.03%, 0.1% or 0.2%, compared with vehicle. This study was conducted at the Sekino Clinical Pharmacology Clinic, Tokyo, Japan, in 2009. E6005-J081-101 (ClinicalTrials.gov Identifier: NCT01179880, JapicCTI-101266): The primary objective was to assess the safety
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and pharmacokinetics of topical application of E6005 ointment (0.01%, 0.03%, 0.1% or 0.2%) compared with vehicle in Japanese men with AD. This study was conducted at the Kyushu Clinical Pharmacology Research Clinic, Fukuoka, Japan, in 2010. Both studies were performed in full compliance with the International Conference on Harmonisation, all applicable Good Clinical Practice guidelines and local regulations in Japan, and were approved by the institutional investigational review boards. All the patients provided written informed consent.
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Study subjects E6005-J081-001: Eligible participants were healthy Japanese adult male volunteers aged 20–45 years with a body mass index between 18.5 and 25.0 kg/m2. Subjects were excluded if they had any skin disease or history of allergy that could jeopardize study results. E6005-J081-101: Japanese patients eligible for Study 101 were men aged 20–65 years with a confirmed clinical diagnosis of mild to severe AD, according to the Japanese Dermatological Association’s ‘‘Guidelines for Management of Atopic Dermatitis’’ (13). Patients needed to have evaluable typical eczema on the posterior trunk (targeted eczema lesions) to explore the efficacy of topical application of E6005 ointment. Patients were excluded if they had additional skin diseases that could jeopardize study results. Patients were required to stop all the topical AD therapies except for white petrolatum (such as topical corticosteroids and calcineurin inhibitors) at least 1 week prior to baseline evaluation, and to discontinue any systemic therapy (antihistamines, systemic corticosteroids, cyclosporine and tacrolimus), phototherapy and photochemotherapy at least 2 weeks prior to baseline evaluation. Study design In Study 001, participants were divided into four cohorts of nine subjects each, according to the concentration of E6005 ointment applied (0.01%, 0.03%, 0.1% or 0.2%). Seven subjects in each cohort were randomly selected to receive E6005 ointment application, while two received vehicle application. Each cohort participated in three testing periods (Figure 1a). In Period 1, 30 mg of the investigational drugs (no treatment; white petrolatum; vehicle; 0.01%, 0.03%, 0.1% and 0.2% E6005) were individually placed in two sets of Finn ChambersÕ (Epitest Ltd Oy, Tuusula, Finland) for patch and photopatch testing. The Finn ChambersÕ were applied to the outer surface of the upper arms on day 1. In Period 2, a simple application of the investigational drug was applied to the posterior trunk at dosages of 1 g in the morning on day 9, 2 g in the morning on day 11 and 5 g in the morning on day 13. In Period 3, on days 15–19, repeated 5 g doses were applied in the morning and at night. The type of ointment applied (E6005 or vehicle) was masked to assessment investigators and to subjects. When no safety concerns arose within a cohort, the next cohort was started with a higher E6005 concentration. Study 101 consisted of four cohorts of 10 patients each. Within each cohort, eight patients were randomly selected to receive application of 5 g of E6005 ointment and two received 5 g of vehicle ointment once on day 1, twice daily on days 2 through 9 and once on day 10. A different concentration of E6005 (0.01%, 0.03%, 0.1% or 0.2%) was applied in each cohort. The ointment was applied first to the targeted eczema lesion on the back, next to other regions of the trunk and finally to the lower limbs if sufficient ointment remained, while avoiding the head, neck and upper limbs. The type of ointment applied (E6005 or vehicle) was masked to assessment investigators and to patients. When no safety concerns arose within a cohort, the next cohort was started with a higher concentration of E6005.
J Dermatolog Treat, 2016; 27(3): 241–246
Assessments In the patch test (skin irritation test), the investigational drugs were applied to the skin for 48 h. Skin reactions were assessed 30 min and 24, 72 and 120 h after removing the Finn ChamberÕ , according to the criteria of the International Contact Dermatitis Research Group (14) and Japanese criteria (15). In the photopatch test (photosensitivity test), the investigational drugs were applied for 24 h. The skin was then exposed to long-wavelength irradiation (UVA, 6 J/cm2). The presence or absence of light urticaria was assessed 30 min after optical irradiation, and the site was then covered with a new empty Finn ChamberÕ for 1 day. Skin reactions were assessed 24, 48, 96 and 144 h after optical irradiation, according to the criteria of the International Contact Dermatitis Research Group (16) and Japanese criteria (15). All the skin reactions were assessed by a physician who was kept blind to the preparation sequence. The assessor did not apply or remove the preparations during the study and was never told the preparation sequence. A photograph of the application site was taken before application and at the time of assessment. The safety profile was assessed with treatment-emergent adverse event reporting, based on the Common Terminology Criteria for Adverse Events (National Cancer Institute, Bethesda, MD, version 4.02), clinical laboratory testing, electrocardiogram recording, vital signs and ophthalmological findings. Measurement of plasma concentrations of E6005 and its metabolite In Study 001, blood samples were collected for assessment of pharmacokinetics before initial treatment, before dosing on days 8, 9, 11, 13, 15 and 19, and at 1-, 2-, 4- and 8-h post-dose on days 15 and 19. In Study 101, blood samples were collected pre-dose on days 1, 2, 5, 10, 11, 12 and 13, and 1-, 2-, 4- and 8-h post-dose on days 1, 5 and 10. Plasma concentrations of E6005 and its major metabolite (the methyl ester hydrolysis product) were quantified with a validated liquid chromatography-tandem mass spectrometry method with a lower limit of quantification of51 ng/ml (11). Statistical analysis Randomization schedules were generated by the SAS RANUNI procedure. All the analyses were performed by Eisai Co., Ltd. using SASÕ for Windows (SAS Institute, Cary, NC, Version 8.2 or later). The full analysis set population was used for all the analyses. Data were summarized descriptively according to treatment. For continuous variables, descriptive statistics are generally presented where applicable (including number of subjects [N], percentage of subjects [%], arithmetic mean [mean] and standard deviation [SD]).
Results Demographics and baseline characteristics In Study 001, 36 healthy male subjects were randomized: 28 to active treatment and 8 to vehicle. Thirty-three of these completed the study and three did not (two because of adverse events and one because of subject choice) (Figure 1a). Demographics and baseline characteristics were generally similar among all the treatment groups (Table 1). In Study 101, 40 male patients were randomized: 32 to active treatment and 8 to vehicle. Thirty-eight of these completed the study. One patient in the 0.03% E6005 ointment treatment group withdrew because of an adverse event; another in the vehicle treatment group withdrew because of AD progression (Figure 1b).
Safety and pharmacokinetic profile of E6005
DOI: 10.3109/09546634.2015.1093587
Period 1
Period 2
Period 3
Days 1–8
Days 9–14
Days 15–22
Patch test and Photopatch test
1 g on day 9, 2 g on day 11, 5 g on day 13
5 g twice daily on days 15–19
Cohort 1 (9 subjects)
0.01% E6005 (7 active, 2 vehicle)
0.01% E6005 (7 active, 2 vehicle)
Cohort 2 (9 subjects)
0.03% E6005 (7 active, 2 vehicle)
0.03% E6005 (7 active, 2 vehicle)
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36 subjects randomized Cohort 3 (9 subjects)
0.1% E6005 (7 active, 2 vehicle)
0.1% E6005 (7 active, 2 vehicle)
1 patient in the active group was withdrawn on day 13 because of subject choice. 1 patient in the vehicle group was withdrawn on day 16 because of an adverse event.
Cohort 4 (9 subjects)
0.2% E6005 (7 active, 2 vehicle)
0.2% E6005 (7 active, 2 vehicle)
1 patient in the active group was withdrawn on day 16 because of an adverse event.
5 g once daily on days 1 and 10, 5 g twice daily on days 2–9
Cohort 1 0.01% E6005 (8 active, 2 vehicle)
Cohort 2 0.03% E6005 (8 active, 2 vehicle)
1 patient in the active group was withdrawn on day 6 because of an adverse event. 1 patient in the vehicle group was withdrawn on day 6 because of progression of atopic dermatitis.
40 subjects randomized Cohort 3 0.1% E6005 (8 active, 2 vehicle)
Cohort 4 0.2% E6005 (8 active, 2 vehicle)
Figure 1. Subject disposition. (a) Design and subject allocation schema for Study 001. (b) Design and subject allocation schema for Study 101.
Demographics and baseline characteristics were generally similar among all the treatment groups (Table 1). Skin irritation and photosensitivity In the skin irritation test in Study 001, four subjects had a positive reaction 30 min after removal of the Finn ChamberÕ (Table 2).
One subject, who experienced application site edema without erythema at the site of the ‘‘no application’’ chamber as a treatment-emergent adverse event, improved without treatment and the reaction was considered not related to the study drug. Three subjects experienced faint application site erythema, one at the site of no treatment, one at the white petrolatum site and one at the 0.2% E6005 site. These were not classified as adverse
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Table 1. Subject demographics and baseline characteristics. E6005
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Characteristics Study 001 Age (years), mean ± SD Height (cm), mean ± SD Weight (kg), mean ± SD BMI (kg/m2), mean ± SD TEWLy (g/m2h), mean ± SD Study 101 Age (years), mean ± SD Height (cm), mean ± SD Weight (kg), mean ± SD BMI (kg/m2), mean ± SD TEWLa (g/m2h), mean ± SD Severity of AD, n Mild Moderate Severe Very severe Duration of AD (years), mean ± SD History of other allergy, n TEWL (g/m2h) at eczema, mean ± SD
Total (n ¼ 36)
Vehicle (n ¼ 8)
0.01% (n ¼ 7)
0.03% (n ¼ 7)
0.1% (n ¼ 7)
0.2% (n ¼ 7)
26.3 ± 4.2 174.69 ± 4.48 66.66 ± 5.24 21.84 ± 1.31 10.87 ± 5.12
25.8 ± 4.5 175.34 ± 4.26 68.83 ± 6.16 22.38 ± 1.57 12.23 ± 5.43
25.4 ± 2.4 172.93 ± 4.42 63.99 ± 3.13 21.40 ± 0.70 8.89 ± 1.56
24.7 ± 3.7 174.59 ± 2.90 65.63 ± 4.61 21.53 ± 1.26 10.31 ± 1.91
27.1 ± 3.7 177.36 ± 5.98 70.50 ± 6.13 22.41 ± 1.82 13.16 ± 9.70
28.7 ± 5.6 173.13 ± 4.11 64.06 ± 2.47 21.40 ± 0.65 9.56 ± 1.70
27.2 ± 7.3 172.20 ± 5.81 66.11 ± 8.96 22.30 ± 2.91 16.96 ± 6.57
27.3 ± 8.6 170.58 ± 8.04 66.53 ± 8.97 22.90 ± 3.11 16.11 ± 5.92
25.5 ± 6.8 170.84 ± 4.85 68.08 ± 7.47 23.39 ± 2.85 16.38 ± 6.06
24.5 ± 3.8 173.10 ± 5.77 62.95 ± 12.19 20.93 ± 3.39 24.23 ± 7.56
29.3 ± 7.5 175.05 ± 4.85 67.28 ± 7.44 21.95 ± 2.37 12.51 ± 3.79
29.4 ± 9.2 171.43 ± 5.20 65.74 ± 9.42 22.35 ± 2.89 15.59 ± 3.26
2 3 2 1 17.71 ± 9.69 2 23.19 ± 5.01
3 5 0 0 22.37 ± 6.02 1 40.64 ± 17.16
10 22 6 2 17.86 ± 8.71 6 29.39 ± 12.50
1 5 1 1 11.30 ± 8.61 1 30.15 ± 12.66
2 4 2 0 16.55 ± 7.34 1 28.81 ± 12.14
2 5 1 0 21.01 ± 8.66 1 24.18 ± 4.83
AD, atopic dermatitis; BMI, body mass index; SD, standard deviation; TEWL, transepidermal water loss. Measured on normal skin.
a
Table 2. Skin irritation test results (International Contact Dermatitis Research Group criteria). E6005 Interpretation Skin irritation test (patch test) No reaction Doubtful reaction (faint erythema only) Weak positive reaction (erythema, infiltration, possibly papules) Strong positive reaction (erythema, infiltration, papules, vesicles) Extreme positive reaction (intense erythema, infiltration, coalescing vesicles) Irritant reaction of a different type
No treatment (n ¼ 36)
White petrolatum (n ¼ 36)
Vehicle (n ¼ 36)
0.01% (n ¼ 36)
0.03% (n ¼ 36)
0.1% (n ¼ 36)
0.2% (n ¼ 36)
34 (94.4%) 1 (2.8%)
35 (97.2%) 1 (2.8%)
36 (100%) 0
36 (100%) 0
36 (100%) 0
36 (100%) 0
35 (97.2%) 1 (2.8%)
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
1 (2.8%)
events, because assessment investigators considered the erythema in these cases to be related to physical contact with the chamber. Photosensitivity testing was negative in all the participants. Safety and tolerability In Study 001, 4 of 28 subjects (14.3%) in the E6005 ointment treatment group and 1 of 8 (12.5%) in the vehicle treatment group had at least one treatment-emergent adverse event (Table 3). One subject, who experienced application site edema in the patch test/ photopatch test, is described earlier. Two subjects in the 0.1% E6005 ointment group experienced increased alanine aminotransferase. One discontinued the study on day 13 because of subject choice and improved without treatment. This elevation was considered to be possibly related to the study drug. The second participant continued the study, improved without treatment and the elevation was considered not related to the study drug. One subject in the 0.2% E6005 ointment treatment group and one
in the vehicle treatment group in Cohort 3 experienced erythema, which occurred in the application area and in a non-application area. Both participants discontinued the study on Day 16, improved without treatment and the reactions were considered not related to the study drug. Deaths and other serious or severe adverse events (Grade 3 or higher) were not observed. Laboratory parameters, vital signs, electrocardiogram parameters and ophthalmological examination findings did not change clinically. In Study 101, 2 of 32 patients (6.3%) in the E6005 ointment treatment group and 1 of 8 (12.5%) in the vehicle treatment group had at least one treatment-emergent adverse event (Table 3). One patient in the 0.03% E6005 ointment treatment group had gout, which occurred in a non-drug application area and improved even after application of the drug. A patient in the 0.2% E6005 ointment treatment group had enterocolitis, which improved despite continuation of the study drug; this patient also had a past history of lower abdominal pain during constipation. Another patient in the vehicle treatment group in Cohort 2 experienced
Safety and pharmacokinetic profile of E6005
0.2% (n ¼ 8)
1 (12.5%)
1 (12.5%)
0
0
0
0
0 0
0.1% (n ¼ 8)
0
0
0
0
0
0
0 0
Pharmacokinetic profile
0 0 1 (12.5%) 0
In both studies, plasma concentrations of E6005 were below the lower limit of quantification (1 ng/ml) at all the sampling points in all the subjects, so it was not possible to obtain any meaningful pharmacokinetic data (Table 4). In Study 001, plasma concentrations of the metabolite M11 were also below the lower limit of quantification (1 ng/ml). In Study 101, the metabolite M11 was detected in the plasma at levels just above the lower limit of quantification (1 ng/ml) and53 ng/ml in 3 of 36 patients (8.3%; in two receiving 0.1% E6005 ointment treatment and in one receiving 0.2% E6005 ointment treatment).
0 0
1 (12.5%) 0 0
0 0
0 1 (14.3%)
Discussion
Medical Dictionary for Regulatory Activities, version 17.1.
a
0 0 0 1 (12.5%)
0 0
0 0
0
0
0
0 0 0 0
0
2 (28.6%)
0
0
0 0 1 (12.5%) 0 0
0
0
0
0 0 0 1 (14.3%) 0
0
0
0
0 0 0 0
0
0
0
0
1 (12.5%) 0 1 (12.5%) 1 (14.3%) 2 (28.6%) 0 1 (14.3%) 1 (12.5%)
Any adverse event Gastrointestinal disorders Enterocolitis General disorders and administration site conditions Application site edema Infections and infestations Kaposi’s varicelliform eruption Investigations Alanine aminotransferase increased Metabolism and nutrition disorders Gout Skin and subcutaneous tissue disorders Dermatitis, atopic Erythema
0.03% (n ¼ 8) 0.01% (n ¼ 8) Vehicle (n ¼ 8) 0.1% (n ¼ 7) 0.03% (n ¼ 7) 0.01% (n ¼ 7) Vehicle (n ¼ 8) MedDRA system organ class and preferred terma
Table 3. Treatment-emergent adverse events.
245
aggravated AD and Kaposi’s varicelliform eruption. None of these adverse events were considered to be related to the study drug. Deaths and other serious or severe adverse events (Grade 3 or higher) were not observed. Laboratory parameters, vital signs, electrocardiogram parameters and ophthalmological examinations did not change clinically.
E6005 E6005
Healthy volunteers (Study 001)
0.2% (n ¼ 7)
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Patients with atopic dermatitis (Study 101)
DOI: 10.3109/09546634.2015.1093587
Neither skin irritation nor photosensitization was observed in subjects treated with E6005 ointment or vehicle ointment, according to Japanese and International Contact Dermatitis Research Group criteria. In addition, there was no specific adverse reaction reported at any E6005 concentration up to 0.2% in this study. These results, including the assessments according to Japanese criteria (15), indicate no safety concerns for skin application of E6005 ointment or vehicle, including skin irritation, phototoxicity or light urticaria. Tacrolimus ointment is widely used in treating AD. The most common adverse effects of tacrolimus ointment are a burning sensation and pruritus at the site of application, occurring during the first few days of treatment (17). In our studies of healthy volunteers and patients with AD, no application site reaction, including burning sensation and pruritus, occurred with use of E6005 ointment. Although our studies did not compare topical E6005 with tacrolimus, our results indicate that E6005 ointment may have a safer profile. In all the healthy volunteers, plasma concentrations of E6005 and its metabolite M11 were below the limit of quantification at all the sampling points during the 5-day repeated application of E6005 ointment. The present findings are consistent with the results obtained when testing healthy skin in rats (11,12). Although E6005 was not detected in the plasma of any patient with AD in the present study, the metabolite M11 was detected in the plasma of three. These results suggest that the stratum corneum is a major barrier to E6005 absorption through the skin in humans (as in rats) and that a small quantity of E6005 is absorbed through eczematous lesions in humans. Furthermore, an in vitro metabolism study using liver microsomes from humans and other animals showed rapid metabolism of E6005 to M11. Together these results suggest low absorption and rapid elimination of E6005 from the systemic circulation in humans. Nausea, vomiting, headache and weight loss, which are the commonly reported adverse reactions associated with other PDE4 inhibitors (9,10), were not observed in the present studies. PDE4 inhibitors are thought to produce a pharmacological response analogous to that of presynaptic a2-adrenoceptor inhibitors by elevating intracellular levels of cAMP in noradrenergic neurons (18). One way to evaluate the emetic potential of this class of drugs is to assess the anaesthesia-reversing effect of PDE4 inhibitors in rats, which do not have a vomiting reflex (19). In a study using this model of emesis, the reversal of anaesthesia with systemic E6005 administration was less potent than that with cilomilast administration (11). Additionally, as discussed earlier,
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Table 4. Number of subjects with plasma concentrations of E6005 or M11 above the lower limit of quantification. Healthy volunteers (Study 001)
Patients with atopic dermatitis (Study 101)
E6005
E6005
Vehicle (n ¼ 8)
0.01% (n ¼ 7)
0.03% (n ¼ 7)
0.1% (n ¼ 7)
0.2% (n ¼ 7)
Vehicle (n ¼ 8)
0.01% (n ¼ 8)
0.03% (n ¼ 8)
0.1% (n ¼ 8)
0.2% (n ¼ 8)
0 0
0 0
0 0
0 0
0 0
0 0
0 0
0 0
0 2 (25.0%)
0 1 (12.5%)
E6005 M11
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The lower limit of quantification was 1.00 ng/ml.
absorption of E6005 is restricted by the stratum corneum, and absorbed E6005 is rapidly metabolized to M11. Furthermore, the metabolite M11 is 100 times weaker than E6005 in suppressing cytokine production by human monocytes, possibly because of its lower cell membrane permeability (11,12). Thus, the adverse reactions commonly reported with the use of other PDE4 inhibitors are expected to be less common with topical E6005 use. This could provide a new treatment option for AD that avoids safety concerns associated with PDE4 inhibitors, while maintaining similar effectiveness (12).
Conclusions
5.
6. 7. 8.
In conclusion, our preliminary data indicate that E6005 ointment is safe and well tolerated in healthy volunteers and in patients with AD, although the results should be interpreted with caution because of the small number of subjects included. Further studies are necessary to evaluate the safety of E6005 ointment applied to larger areas throughout the body for longer periods.
10.
Acknowledgements
11.
We would like to thank the investigators and their teams at the Sekino Clinical Pharmacology Clinic and the Kyushu Clinical Pharmacology Research Clinic. Gratitude is expressed to Professor Akiyoshi Fukamizu (University of Tsukuba) for his critical reading of the article.
12.
9.
Declaration of interest F.O., M.N., S.H. and H.A. are employed by Eisai Co., Ltd., which holds patents on E6005 (US7939540, EP1992622, JP4778550). Eisai Co, Ltd. manufactured the E6005 ointment, sponsored the present studies, was involved in the design and execution of the studies; in the collection, analysis and interpretation of data; and in the preparation, review and approval of the article prior to submission.
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