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.

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

Boxplots of C_ss versus actual treatment during VC period, stratified by geographical region and baseline IGA score, in phase III studies combined. BID twice daily, C_ss steady-state plasma concentration, IGA Investigator’s Global Assessment, VC vehicle-controlled

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

Forest plot of effects of covariates of interest on C_ss of ruxolitinib in phase III studies combined. BSA body surface area, C_ss steady-state plasma concentration, IGA Investigator’s Global Assessment

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

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, C_ss steady-state concentration, Q1 to Q4 1st to 4th quartiles of ruxolitinib C_ss during VC period, PK pharmacokinetic, VC vehicle-controlled