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.

Generalized granuloma annulare: A widespread response to limited application of compounded 2% topical tofacitinib

“…Among patients with atopic dermatitis who were applying tofacitinib 2% ointment over limited areas, 24% had plasma concentrations of the drug greater than 1 ng/mL a mean of 0.6 hours later. 8 For comparison, the mean concentration after a 5-mg oral dose, as used in rheumatoid arthritis, is approximately 17.0 ng/mL. 8 The plasma concentration with topical treatment in some patients may be sufficient to produce a therapeutic response at distal lesions.…”

“…8 For comparison, the mean concentration after a 5-mg oral dose, as used in rheumatoid arthritis, is approximately 17.0 ng/mL. 8 The plasma concentration with topical treatment in some patients may be sufficient to produce a therapeutic response at distal lesions.…”

Drug Repurposing in Dermatology: Molecular Biology and Omics Approach

“…The Janus kinase (JAK) inhibitor, tofacitinib (28), was developed originally for management of rheumatoid arthritis, ulcerative colitis and other autoimmune diseases, but it was repurposed for psoriasis and atopic dermatitis since JAK was found to be contributing in the pathogenesis of these diseases, and currently, several clinical trials were performed to assess its clinical significance and concluded that response rates in tofacitinib-treated group were significantly higher compared to that in placebo [39][40][41].…”

Research Techniques Made Simple: An Introduction to Drug Discovery for Dermatology

“…By avoiding treatment of pregnant mothers, the primary side effect (birth defects) is avoided. A recent study of the topical pharmacokinetics of tofacitinib (Purohit et al, 2019) illustrates a general observation that topical application of a drug to a body surface area of <30% rarely leads to a systemic drug concentration sufficient to lead to side effects. Repositioning can therefore be a particularly effective strategy in dermatology.…”