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

Xiaohua Gong, Xuejun Chen, Michael E Kuligowski, Xing Liu, Xiang Liu, Evan Cimino, Ryan McGee, Swamy Yeleswaram, Xiaohua Gong, Xuejun Chen, Michael E Kuligowski, Xing Liu, Xiang Liu, Evan Cimino, Ryan McGee, Swamy Yeleswaram

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 (Css) increased with cream strength in a less-than-dose-proportional manner. In the phase III studies, overall mean (standard deviation [SD]) Css 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 Css: 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 Css 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.

Conflict of interest statement

All authors are employees and shareholders of Incyte Corporation.

Figures

Fig. 1
Fig. 1
Ruxolitinib trough concentration over time after treatment with the indicated concentrations of ruxolitinib cream in phase III studies combined. BID twice daily, LTS long-term safety, VC vehicle-controlled
Fig. 2
Fig. 2
Boxplots of Css versus actual treatment during VC period, stratified by geographical region and baseline IGA score, in phase III studies combined. BID twice daily, Css steady-state plasma concentration, IGA Investigator’s Global Assessment, VC vehicle-controlled
Fig. 3
Fig. 3
Steady-state concentration of ruxolitinib, by covariates of potential interest in phase III studies combined. API active pharmaceutical ingredient, BSA body surface area, EASI Eczema Area and Severity Index
Fig. 4
Fig. 4
Forest plot of effects of covariates of interest on Css of ruxolitinib in phase III studies combined. BSA body surface area, Css steady-state plasma concentration, IGA Investigator’s Global Assessment
Fig. 5
Fig. 5
Bioavailability versus %BSA treated by treatment arm and geographical region in phase III studies combined. BID twice daily, BSA body surface area
Fig. 6
Fig. 6
Mean (95% CI) platelet count over time after application of ruxolitinib cream in the phase III studies combined. BQL ruxolitinib cream treatment but PK samples below the quantification limit, Css steady-state concentration, Q1 to Q4 1st to 4th quartiles of ruxolitinib Css during VC period, PK pharmacokinetic, VC vehicle-controlled

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