Maximal Usage Pharmacokinetic (PK) and Safety Study (Study 107)

The objective of this phase I study was to evaluate the systemic exposure and characterize the PK profile of roflumilast and its major N-oxide metabolite, when dosed under maximal usage conditions, e.g., in patients with psoriasis with extensive body surface area (BSA) involvement and at the upper range of disease severity. Safety and tolerability were also assessed in this open-label, single-arm, 2-week study of roflumilast cream 0.3% in adolescent and adult patients with chronic plaque psoriasis (ClinicalTrials.gov identifier: NCT04279119).

Enrolled patients included those diagnosed with psoriasis of at least 3 months’ duration, involving at least 10% of BSA in adolescents (12–17 years) and at least 20% of BSA (excluding the scalp) in adults (≥ 18 years of age), and Investigator Global Assessment score of at least moderate (3) at baseline. For this maximal usage study, a minimum of 20% BSA was chosen because it is considered the maximal feasible BSA for topical application. Additional inclusion and exclusion criteria are provided in Electronic Supplementary Table 1.

Roflumilast cream 0.3% contains 50% water, 25% diethylene glycol monoethyl ether (Transcutol® P), 15% moisturizers (petrolatum and isopropyl palmitate), hexylene glycol, emulsifiers, and methylparaben and propylparaben as preservatives. It is formulated at physiological skin pH (5.5) without propylene glycol, polyethylene glycol, ethanol, or fragrances. Roflumilast cream was applied once daily (each evening) to areas with plaques, including body, face, and intertriginous/genital areas, but excluding the scalp. Patients were to apply roflumilast cream (2 mg/cm2) to all treated areas throughout the study, even if treatment areas cleared, and to any new lesions that appeared during the study.

Blood samples for PK analysis were obtained before application of roflumilast on Days 1 and 15; 1, 2, 4, 8, and 24 h post-dose on Days 1 and 15; and 7, 14, and 21 days after the last application (Weeks 3, 4, and 5; optional for adolescents). PK parameters included maximum concentration (Cmax), area under the curve until the last quantifiable timepoint (AUClast), time of maximum concentration (Tmax), and elimination half-life (t½) for roflumilast and its N-oxide metabolite. Cmax and AUClast values were normalized per dose to allow more accurate assessment of differences in adolescents and adults.

Local tolerability was assessed by the investigator at Baseline and before the last application at Day 15; patients assessed the level of stinging and burning at 10–15 min after the first and last application of roflumilast. Safety assessments included clinical laboratory, 12-lead electrocardiogram (ECG), vital signs, weight, Patient Health Questionnaire depression scale (PHQ-8 and modified PHQ-A), and Columbia-Suicide Severity Rating Scale (C-SSRS). BSA was assessed at Baseline and Day 15.

Assessment of Roflumilast and Roflumilast N-Oxide Levels in Skin from a Phase I/IIa Study (Study 101)

Levels of roflumilast and roflumilast N-oxide in the skin were assessed as part of a phase I/IIa study in two cohorts of patients with chronic plaque psoriasis (ClinicalTrials.gov identifier: NCT03392168). The safety and efficacy results of this study have been published [18]. Skin samples could be obtained in Cohort 2, which was a parallel-group, double-blind, vehicle-controlled study of once-daily roflumilast cream 0.5% and 0.15% for 28 days in patients with chronic plaque psoriasis for a duration > 6 months and ≤ 5% BSA involvement. Patients could opt to allow a punch biopsy (4 mm) for assessment of levels of roflumilast and roflumilast N-oxide in skin, taken from a target plaque on Day 28. The punch biopsy included the epidermis, dermis, and subcutaneous skin layers. Plasma concentrations of roflumilast and roflumilast N-oxide were assessed at Day 28 before application, and 1, 2, 4, 6 and 24 h after the last dose.

Phase III DERMIS-1 and DERMIS-2 PK Assessment (Studies 301 and 302)

DERMIS-1 (ClinicalTrials.gov identifier: NCT04211363) and DERMIS-2 (ClinicalTrials.gov identifier: NCT04211389) were identical, parallel-group, randomized (2:1), double-blind, vehicle-controlled trials of roflumilast cream 0.3% or vehicle applied once daily for 8 weeks to patients with chronic plaque psoriasis affecting 2–20% BSA. The safety and efficacy results of the DERMIS trials have been published [13]. Male or female children (2–11 years), adolescents (12–17 years), and adults (≥ 18 years) with chronic plaque psoriasis could be enrolled.

Roflumilast cream 0.3% or vehicle was applied once daily to all lesions (excluding the scalp) as identified by the investigator, even if lesions cleared during the study. New lesions were to be treated as well. Predose (Ctrough) plasma samples for roflumilast and roflumilast N-oxide were obtained at Baseline, Week 4, and Week 8. Ctrough concentrations were assessed from observed data, and given the flat PK profile of topical roflumilast, the AUC from time zero to 24 h (AUC24) was extrapolated by multiplying the predose concentration value by 24.

PK Analyses

In Study 107, the PK analysis was performed for roflumilast and the roflumilast N-oxide metabolite using noncompartmental analysis and following the Linear Trapezoidal Linear Interpolation calculation method. A minimum of three consecutive quantifiable concentrations were required to include a patient in the analysis. Cmax and the corresponding Tmax values were determined by direct assessment of the concentration versus time data. Nominal dose values and sampling times were used for PK parameter estimations. The terminal elimination rate constant (lambda z, λz) was calculated following the last dose administered using the actual analysis day values. The Week 2, 24-h plasma concentration value, along with any quantifiable concentration at 1, 2, and 3 weeks post the last dose administered, were used to derive a λz value by determining the slope of the regression line of the natural log-transformed concentrations versus time. Data from patients with at least two values were used. The terminal half-life (t½) was calculated as ln (2)/λz. Analysis of the PK data collected was performed with a CFR 21 Part 11 compliant software package (Phoenix WinNonlin version 8.3; Certara, Princeton, NJ, USA), which is in full compliance with International Council for Harmonization Good Clinical Practice.

Drug Analysis

Roflumilast and roflumilast N-oxide plasma concentrations were measured using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay. The lower limit of quantification (LLOQ) was 0.100 ng/mL for roflumilast and roflumilast N-oxide. Skin samples from punch biopsies were immediately frozen until samples were assayed at a central location. Roflumilast and roflumilast N-oxide concentrations were quantified in skin homogenates using an LC-MS/MS assay for assessment of tissue concentrations of roflumilast and roflumilast N-oxide.

Study Ethics

These studies were conducted in accordance with the ethical principles set forth in the Declaration of Helsinki and the International Council for Harmonization harmonized tripartite guideline regarding Good Clinical Practice (2016 guidance). Approval by the investigational review board was obtained from each investigator’s institution and written informed consent or assent was obtained before enrollment. In the skin-level assessment from the phase I/IIa study (Study 101), the protocol was approved by Research Review Board, Inc., Richmond Hill, ON, Canada, for all sites [18].