Dataset Information

Pharmacokinetics of Ruxolitinib in Patients with Atopic Dermatitis Treated With Ruxolitinib Cream: Data from Phase II and III Studies.

ABSTRACT:

Background

Pathogenesis of atopic dermatitis (AD) involves the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway. A cream formulation of ruxolitinib, a potent selective JAK1/JAK2 inhibitor, was developed for topical delivery.

Method

Pharmacokinetic data were obtained from three double-blind, vehicle-controlled studies in patients with AD: a phase II study with ruxolitinib cream 0.15%, 0.5%, or 1.5% once daily or 1.5% twice daily (BID), and two phase III studies with 0.75% or 1.5% BID. Effects of baseline characteristics on pharmacokinetics were examined. Correlations were attempted between plasma concentrations and change in hematological parameters over time.

Results

Ruxolitinib plasma concentrations at steady-state (C_ss) increased with cream strength in a less-than-dose-proportional manner. In the phase III studies, overall mean (standard deviation [SD]) C_ss after ruxolitinib cream 0.75% and 1.5% BID (23.8 [35.0] and 35.7 [55.0] nM) were a fraction of the half-maximal inhibitory concentration for thrombopoietin-stimulated phosphorylated STAT3 inhibition (281 nM), a JAK/STAT signaling marker. Three covariates were identified for C_ss: dose, percent body surface area (%BSA) treated, and baseline Investigator's Global Assessment score. Mean (SD) bioavailability of ruxolitinib cream 1.5% BID was 6.22% (7.66%). There were no correlations between C_ss and any hematological changes except for a transient increase in platelets at week 2.

Conclusions

Plasma ruxolitinib concentrations after treatment with topical ruxolitinib cream in patients with up to 20% BSA affected by AD are not expected to lead to systemic plasma concentrations that may be associated with adverse effects commonly associated with oral JAK inhibitors. CLINICALTRIALS.GOV: NCT03011892; NCT03745638; NCT03745651.

SUBMITTER: Gong X

PROVIDER: S-EPMC8200345 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundAtopic dermatitis is a chronic inflammatory skin disease that can negatively impact work productivity and daily activities. Ruxolitinib cream, a Janus kinase inhibitor, demonstrated efficacy and safety in patients with atopic dermatitis in two phase III studies (TRuE-AD1 and TRuE-AD2).ObjectiveThis post hoc analysis sought to describe the effects of ruxolitinib cream on work productivity and activity impairment from pooled data from the phase III studies, to estimate indirect costs due to atopic dermatitis, and to estimate the incremental cost savings with ruxolitinib cream versus vehicle cream.MethodsPatients in both studies were ≥ 12 years old with atopic dermatitis for ≥ 2 years, an Investigator's Global Assessment score of 2 or 3, and a 3-20% affected body surface area at baseline. Patients were randomized 2:2:1 to receive ruxolitinib cream (0.75% or 1.5%) or vehicle cream for 8 weeks. Patient self-reported productivity in the efficacy-evaluable population was assessed at weeks 2, 4, and 8 using the Work Productivity and Activity Impairment Questionnaire-Specific Health Problem version 2.0. Statistical significance for the two doses versus vehicle was calculated using an analysis of covariance. Work Productivity and Activity Impairment overall work impairment scores were converted to a model of costs per employed patient due to lost productivity and incremental cost savings from ruxolitinib cream treatment using a human capital approach.ResultsOf 1249 patients enrolled (median age, 32 years; female sex, 61.7%), 1208 were included in the efficacy-evaluable population. Patients applying 0.75% or 1.5% ruxolitinib cream had significant changes in overall work impairment (- 17.9% [0.75% strength] and - 15.0% [1.5% strength] vs - 5.7% for vehicle; p < 0.0001 for both) and daily activity impairment (- 20.6% [0.75% strength] and - 21.5% [1.5% strength] vs - 10.6% for vehicle; p < 0.0001 for both). These corresponded to estimated lost productivity costs in 2021 US dollars of $1313 (0.75% strength) and $1242 (1.5% strength) versus $2008 (vehicle) over the 8-week trial period. Compared with a patient receiving vehicle, incremental annual indirect cost savings were estimated to be $5302 with 0.75% ruxolitinib cream and $4228 with 1.5% ruxolitinib cream.ConclusionsRuxolitinib cream therapy is associated with improved work productivity and daily activity compared with vehicle and is estimated to reduce the indirect cost burden on the patient.Clinical trial registrationClinicalTrials.gov identifiers: NCT03745638 (registered 19 November, 2018) and NCT03745651 (registered 19 November, 2018).

Project description:IntroductionStandard therapy for patients with mild to moderate atopic dermatitis (AD) typically includes topical therapies; however, patients with more extensive AD and/or AD refractory to topical therapy may benefit from systemic treatment. Ruxolitinib cream monotherapy has demonstrated superior antipruritic and anti-inflammatory effects versus vehicle in patients with mild to moderate AD, and long-term disease control with as-needed use. Here, efficacy/safety of 1.5% ruxolitinib cream through 52 weeks was assessed in a subset of patients with moderate and/or more extensive disease.MethodsThis post hoc analysis of TRuE-AD1/TRuE-AD2 included patients who, at baseline, had Investigator's Global Assessment (IGA) score of 3, Eczema Area and Severity Index (EASI) ≥ 16, and affected body surface area (BSA) ≥ 10% (higher severity of disease threshold subgroup). Disease control and safety were assessed.ResultsOf 1249 patients in the overall population, 78 (6.2%) met all higher severity of disease threshold criteria (continuous-use vehicle-controlled period: 1.5% ruxolitinib cream, n = 32; vehicle, n = 13); 28 and 4 of these patients, respectively, continued as-needed 1.5% ruxolitinib cream during the long-term safety (LTS) period. At week 8 (continuous-use), IGA-treatment success (IGA 0/1, with ≥ 2-grade improvement from baseline) was achieved by 19/32 (59.4%) patients applying 1.5% ruxolitinib cream versus no patients applying vehicle. In the LTS period, those achieving clear/almost clear skin increased from 19/28 patients (67.9%; continuous-use: week 8) to 18/23 patients (78.3%; as-needed use: week 52) in patients applying ruxolitinib cream from day 1. Ruxolitinib cream was well tolerated, with few application site reactions, regardless of disease severity threshold. Efficacy and safety results were similar to the overall study population.ConclusionPatients with AD who meet standard disease severity eligibility criteria for systemic therapy may achieve IGA-treatment success with clear/almost clear skin with continuous-use ruxolitinib cream, and maintain long term-disease control with as-needed ruxolitinib cream monotherapy.Trial registration numberNCT03745638/NCT03745651.

Project description:BackgroundRuxolitinib cream is a topical formulation of ruxolitinib, an inhibitor of Janus kinase 1 and Janus kinase 2.ObjectiveWe aimed to determine the safety, tolerability, and bioavailability of 1.5% ruxolitinib cream under maximum-use conditions in patients with atopic dermatitis. Efficacy was evaluated as an exploratory objective.MethodsEligible patients aged ≥ 12-65 years with atopic dermatitis, an Investigator's Global Assessment score ≥ 2, and ≥ 25% affected body surface area were enrolled in an open-label, maximum-use phase I study conducted in the USA and Canada. Patients applied 1.5% ruxolitinib cream twice daily to lesions identified at baseline for the first 28 days and continued use only on active lesions for an additional 28 days (extension period). Safety was assessed by frequency, duration, and severity of treatment-emergent adverse events. Plasma concentrations of ruxolitinib and pharmacokinetic parameters were assessed as secondary endpoints.ResultsOverall, 41 patients (median age, 17 years; 51% male) were enrolled and 37 (90.2%) entered the extension period, all of whom completed the study. Treatment-emergent adverse events were reported in 13 patients (31.7%). Treatment-related adverse events were reported in four patients (9.8%). The mean (standard deviation) steady-state plasma concentration was 104 (309) nM during the first 28 days, well below the half-maximal inhibitory concentration of Janus kinase-mediated myelosuppression in the bone marrow (281 nM), and decreased further during the extension period. Higher plasma concentrations were detected in a few patients who were treated for a very high affected body surface area. At day 56, 94.6% of patients achieved ≥ 75% improvement in the Eczema Area and Severity Index.ConclusionsUnder maximum-use conditions, ruxolitinib cream was generally well tolerated, with approximately one-third of patients experiencing treatment-emergent adverse events and few treatment-related adverse events. The mean steady-state plasma concentration of ruxolitinib was well below the level expected to affect bone marrow production of blood cells, with a small number of patients exhibiting higher plasma concentrations. In addition, ruxolitinib cream showed a high level of efficacy in patients with atopic dermatitis involving ≥ 25% affected body surface area.ClinicaltrialsGov identifierNCT03920852.

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