背景:虽然大多数特应性皮炎(AD)患者通过dupilumab治疗实现了疾病控制,患者获得明确疾病的可变性。这些反应的预测因素目前尚不清楚。开发了综合模型来评估dupilumab在儿童中的暴露-反应(E-R)关系,青少年,成人AD
方法:收集了来自六项II期和III期临床研究的数据(2,366名成年人[>18岁],243名青少年[≥12至<18岁]和359名儿童[≥6至<12岁])进行模型开发。使用湿疹面积和严重程度指数(EASI)和研究者全球评估(IGA)评估疗效。间接反应模型用于将功效和功能性血清dupilumab浓度的测量联系起来。评估个体安慰剂校正反应的协变量。模拟临床试验方案以比较不同年龄组的E-R关系。没有探索安全性。
结果:校正安慰剂反应和dupilumab暴露的差异后:1)年龄较大,体重较高,较低的基线胸腺和活化调节趋化因子,亚洲种族与EASI反应略低有关,在IGA反应方面未发现明确的协变量;2)临床试验模拟通常显示,与患有重度和中度AD的成人和青少年相比,儿童在给定dupilumab浓度下的反应略高.
结论:共同测试的协变量解释了AD患者dupilumab反应的一些变异性。所有年龄组的患者都对dupilumab表现出足够的反应;然而,在同等浓度下,与成人和青少年相比,儿童的药物作用略高.
BACKGROUND: While the majority of patients with atopic dermatitis (AD) achieve disease control with dupilumab treatment, there is variability in which patients achieve clear disease. The predictors of these responses are currently unclear. Integrated models were developed to evaluate the exposure-response (E-R) relationship of dupilumab in children, adolescents, and adults with AD.
METHODS: Data from six Phase II and III clinical studies were pooled (2,366 adults [> 18 years], 243 adolescents [≥ 12 to < 18 years] and 359 children [≥ 6 to < 12 years]) for model development. Efficacy was assessed using the Eczema Area and Severity Index (EASI) and Investigator\'s Global Assessment (IGA). Indirect response models were applied to link measures of efficacy and functional serum dupilumab concentrations. The covariates on individual placebo-corrected response were assessed. Clinical trial scenarios were simulated to compare E-R relationships across age groups. Safety was not explored.
RESULTS: After correcting for differences in placebo response and dupilumab exposure: 1) older age, higher body weight, lower baseline thymus and activation-regulated chemokine, and Asian race were associated with slightly lower EASI response, and no clear covariates were identified on IGA response; 2) clinical trial simulations generally showed slightly higher response at a given dupilumab concentration in children compared to adults and adolescents with severe and moderate AD.
CONCLUSIONS: The collectively tested covariates explain some of the variability in dupilumab response in patients with AD. Patients in all age groups showed adequate response to dupilumab; however, children showed slightly higher drug effects compared to adults and adolescents at equivalent concentrations.