Systemic Tofacitinib Concentrations in Adult Patients With Atopic Dermatitis Treated With 2% Tofacitinib Ointment and Application to Pediatric Study Planning

Abstract

Atopic dermatitis is a chronic eczematous, pruritic, inflammatory skin condition affecting children and adults. Tofacitinib is a Janus kinase inhibitor. The efficacy, safety, and pharmacokinetics of 2% tofacitinib ointment twice daily have been evaluated in a 4-week phase 2a multisite randomized, double-blind, vehicle-controlled, parallel-group study (NCT02001181) in adult patients with mild to moderate atopic dermatitis and 2% to 20% body surface area (BSA) involvement. Tofacitinib ointment demonstrated significantly greater efficacy versus vehicle for all efficacy end points and had an acceptable safety profile. Predose and postdose pharmacokinetic samples were collected in week 2 and week 4. The objective of this analysis was to assess if predicted mean tofacitinib concentrations with topical application at higher treated BSA across age groups would exceed relevant concentration thresholds based on oral doses of tofacitinib. In this analysis, the pharmacokinetic concentrations were characterized using a linear mixed-effects model. The model was used to predict concentrations for adults with higher (>20%) treatable BSA. Adult concentrations were used to extrapolate concentrations to a pediatric population (2 to 17 years) using allometric principles. The predicted systemic concentrations for 2% tofacitinib ointment in both adult and pediatric populations at treated BSA ≤50% for a mild to moderate atopic dermatitis population did not exceed those reported for the 10th percentile of observed oral tofacitinib 5-mg twice-daily doses in patients with moderate to severe plaque psoriasis. The methodology described will enable analysis and prediction of systemic concentrations for topical agents.

Keywords: atopic dermatitis; pharmacokinetics; systemic concentration; tofacitinib; topical.

Figure 1

Relationship between the observed systemic tofacitinib concentration (predose and postdose) in week 2 and week 4 and treated BSA in adults with mild to moderate atopic dermatitis. The solid line represents the naive‐pooled linear regression fit of the data. BSA, body surface area.

Figure 2

(A) Box‐and‐whisker plot of application rate of 2% tofacitinib ointment from day 1 to week 2 and from week 2 to week 4. (B) Relationship between tofacitinib application rate and treated baseline BSA from day 1 to week 2 and from week 2 to week 4. The solid line represents the naive‐pooled linear regression fit of the data; the dashed line represents the median application rate (mg/cm²). BSA, body surface area.

Figure 3

(A) Goodness‐of‐fit plots for the final linear mixed‐effects model (model 4; equation 5). (B) Solid line represents the mean prediction from model 4; the dashed lines represent the 95% bootstrap confidence interval of the mean prediction.