Pfizer Inc, Groton, Connecticut, USA.
Pfizer Inc, New York, New York, USA.
J Clin Pharmacol. 2020 Oct;60(10):1344-1354. doi: 10.1002/jcph.1624. Epub 2020 May 20.
Crisaborole ointment, 2%, is a nonsteroidal phosphodiesterase 4 inhibitor for the treatment of mild to moderate atopic dermatitis. Results from 2 randomized, double-blind, vehicle-controlled phase 3 studies showed that twice-daily crisaborole in children and adults with mild to moderate atopic dermatitis was efficacious and well tolerated. Initial pharmacokinetics (PK) studies of crisaborole indicated absorption with measurable systemic levels of crisaborole. The current analysis was conducted to correlate steady-state systemic exposure parameters with ointment dose and identify covariates impacting PK parameters in healthy participants and patients with atopic dermatitis or psoriasis. A nonlinear regression analysis was conducted using ointment dose and noncompartmental PK parameters at steady state (area under the curve [AUC ] and maximum concentration [C ]). PK data were available from 244 participants across 6 clinical studies (AUC , N = 239; C , N = 241). Disease condition had the greatest impact on slope in both models, corresponding to 2.5-fold higher AUC and C values at a given ointment dose in patients with atopic dermatitis or psoriasis relative to healthy participants. Disease severity, race/ethnicity, and sex had marginal effects on AUC and C . Systemic exposures were similar across age groups ≥2 years of age when the same percentage of body surface area (%BSA) was treated. Predictive performance plots for AUC and C for different age groups demonstrated that the models adequately describe the observed data. Model predictions indicated that systemic exposure to crisaborole in pediatric patients (2-17 years) is unlikely to exceed systemic exposure in adults (≥18 years), even at the highest possible ointment dose corresponding to a %BSA of 90.
2%的克立硼罗软膏是一种非甾体磷酸二酯酶 4 抑制剂，用于治疗轻度至中度特应性皮炎。两项随机、双盲、赋形剂对照的 3 期研究结果表明，对于轻度至中度特应性皮炎的儿童和成人，每天两次使用克立硼罗软膏是有效且耐受良好的。克立硼罗的初步药代动力学（PK）研究表明，其具有可测量的全身水平的吸收。目前的分析旨在将稳态全身暴露参数与软膏剂量相关联，并确定影响健康参与者和特应性皮炎或银屑病患者 PK 参数的协变量。使用软膏剂量和稳态下的非房室 PK 参数（曲线下面积[AUC]和最大浓度[C]）进行非线性回归分析。在 6 项临床研究中，共有 244 名参与者提供了 PK 数据（AUC，N=239；C，N=241）。在这两个模型中，疾病状况对斜率的影响最大，与健康参与者相比，特应性皮炎或银屑病患者在给定软膏剂量时，AUC 和 C 值高出 2.5 倍。疾病严重程度、种族/民族和性别对 AUC 和 C 有一定影响。当相同的体表面积（%BSA）被治疗时，≥2 岁的年龄组的系统暴露情况相似。不同年龄组 AUC 和 C 的预测性能图表明，这些模型可以充分描述观察到的数据。模型预测表明，儿童患者（2-17 岁）的克立硼罗全身暴露不太可能超过成年患者（≥18 岁）的全身暴露，即使在可能的最高软膏剂量下，对应的体表面积为 90%。
