Regeneron Pharmaceuticals, Inc., Tarrytown, New York, USA.
Department of Dermatology, Oregon Health & Science University, Portland, Oregon, USA.
Clin Transl Sci. 2022 Oct;15(10):2342-2354. doi: 10.1111/cts.13363. Epub 2022 Aug 20.
The pharmacokinetics (PKs) and exposure-efficacy of dupilumab have not been fully described for adults with atopic dermatitis (AD). Our objectives were to analyze the PKs and exposure-efficacy of dupilumab in adults with AD and compare the results of Japanese and overall populations. Adults with moderate-to-severe AD were randomly assigned to dupilumab (300 mg weekly [qw] or every 2 weeks [q2w], 200 mg q2w, 300 mg every 4 weeks [q4w], or 100 mg q4w) or placebo for 16 weeks in a randomized, double-blind, placebo-controlled, dose-ranging phase IIb trial (NCT01859988). This analysis included 379 patients (58 Japanese). Functional dupilumab concentrations increased in a dose-dependent manner; at lower concentrations, increases were greater than dose-proportional because of nonlinear, target-mediated clearance. Dupilumab pharmacokinetics were comparable in Japanese and non-Japanese patients with similar body weights. Week 16 efficacy parameters, including Investigator's Global Assessment score 0/1, greater than or equal to 75% reduction from baseline in the Eczema Area and Severity Index (EASI), and percentage change from baseline in EASI and pruritus Numerical Rating Scale, generally increased with week 16 trough concentration; the plateau of these exposure-efficacy relationships occurred for most patients at exposures associated with the 300 mg q2w and 300 mg qw regimens. Japanese ethnicity did not remain in the population PK model as covariate with or without accounting for body weight differences. In Japanese and non-Japanese patients, efficacy responses increased with week 16 dupilumab trough concentrations in a similar manner. Dupilumab 300 mg qw and q2w regimens were recommended for further evaluation in larger phase III studies.
变应性皮炎患者的度普利尤单抗药代动力学（PK）和暴露-疗效尚未完全描述。我们的目的是分析变应性皮炎成人患者度普利尤单抗的 PK 和暴露-疗效，并比较日本和总体人群的结果。中重度特应性皮炎成人患者随机接受度普利尤单抗（每周 300mg[qw]或每 2 周 300mg[q2w]、每 2 周 200mg、每 4 周 300mg[q4w]或每 4 周 100mg[q4w]）或安慰剂治疗 16 周，这是一项随机、双盲、安慰剂对照、剂量范围的 IIb 期试验（NCT01859988）。该分析包括 379 名患者（58 名日本人）。功能性度普利尤单抗浓度呈剂量依赖性增加；在较低浓度下，由于非线性、靶向介导清除，增加量大于剂量比例。日本人与体重相似的非日本人患者的度普利尤单抗药代动力学相似。第 16 周的疗效参数，包括研究者全球评估评分 0/1、Eczema Area and Severity Index（EASI）基线下降≥75%、EASI 和瘙痒数字评定量表基线变化百分比，通常随着第 16 周谷浓度增加而增加；对于大多数患者，这些暴露-疗效关系的平台发生在与 300mg q2w 和 300mg qw 方案相关的暴露量。在包含或不包含体重差异的人群 PK 模型中，日本人种未作为协变量保留。在日本人和非日本人患者中，疗效反应以类似的方式随第 16 周度普利尤单抗谷浓度增加而增加。建议进一步评估度普利尤单抗 300mg qw 和 q2w 方案在更大规模的 III 期研究中。
