512 Patient and disease characteristic predictors of systemic exposure to crisaborole

Abstract

Crisaborole ointment, 2%, is a nonsteroidal phosphodiesterase 4 inhibitor for the treatment of mild-to-moderate atopic dermatitis (AD). Initial pharmacokinetic (PK) studies of crisaborole showed absorption with measurable systemic levels of crisaborole. A nonlinear regression analysis using ointment dose and noncompartmental PK parameters at steady state (area under the curve [AUCss] and maximum concentration [Cmaxss]) was conducted to correlate systemic exposure parameters with ointment dose and clearance difference between patient subpopulations. Data from 8 clinical studies were included: 3 phase 1 studies in healthy adults, 2 phase 1b studies in patients aged 12-17 years with mild-to-moderate AD, 1 phase 1 study in Japanese patients with mild-to-moderate AD, 1 phase 4 study in children aged 3-24 months with mild-to-moderate AD, and 1 phase 1b study in adults with mild-to-very severe psoriasis. The base model describing the relationship between systemic exposure and ointment dose was defined with a slope and intercept fixed to 0, with weight as covariate included as an allometric function to account for clearance differences. Race, sex, disease condition (healthy volunteer, AD, or psoriasis), baseline disease severity, and age were tested as covariates. PK data were available from 271 participants (AUCss, N=264; Cmaxss, N=267). Mean participant age was 28.6 years, and median ointment dose was 15,800 mg (range, 4700-47,100 mg). Disease condition had the greatest impact on slope in both models, corresponding to ∼2.5-fold higher AUCss and Cmaxss values at a given ointment dose in patients with AD or psoriasis relative to healthy volunteers. Disease severity, race, and sex had marginal effects on AUCss and Cmaxss. Model predictions indicated that, at similar treated percentage of body surface area, crisaborole systemic exposures across age groups are expected to be in a similar range, and systemic exposures in children (>3 months of age) at maximum possible dose are unlikely to exceed the systemic exposures at the maximum possible dose in adults.