Dupilumab在中至重度哮喘儿童中的药代动力学及其对2型生物标志物的影响
2023/07/21
摘要
背景：2型炎症在哮喘患儿中很常见。Dupilumab是一种人类抗体，它能阻断白细胞介素-4和-13的信号传导，而白细胞介素-4和-13是2型炎症的关键和核心驱动因素。在LIBERTY ASTHMA VOYAGE (NCT02948959)研究中，Dupilumab减少了6至11岁未控制的中重度哮喘患儿的严重哮喘加重并改善了肺功能。
目的：评估VOYAGE中2型哮喘儿童中Dupilumab的药代动力学和2型生物标志物的变化。
方法：患者被随机分配接受每2周1次dupilumab 100 mg(≤30 kg)或200 mg (30 kg)或安慰剂治疗，共52周。每次访视时评估Dupilumab浓度和2型生物标志物的变化。
结果：血清中Dupilumab的浓度在第12周达到稳态，接受Dupilumab100mg/2周和200mg/2周治疗的儿童的平均浓度分别为51.2mg/L和79.4mg/L（成人和青少年的治疗范围：29-80 mg/L）。不同治疗方案的2型生物标志物降低率相当，接受dupilumab治疗的患者的降低率高于接受安慰剂治疗的患者。在dupilumab 100mg和200mg每2周治疗的患儿中，第52周时血清总免疫球蛋白E的中位数变化百分比(q1～q3)中位数分别为-78.6%(-86.3～-69.80)和-78.6%(-84.9～-70.1)，胸腺和活化调节趋化因子分别为-53.6%(-66.4～-34.6)和-43.7% (-58.6～-28.5);血嗜酸性粒细胞分别为-25.7%(-60.0～27.6)和-33.3%(-60.6～16.6)，呼出气一氧化氮分别为-47.7%(-73.8～18.9)和-55.6%(-73.6～-20.0)。
结论：分级给药方案达到了Dupilumab治疗范围内的平均浓度。2型生物标志物水平的中位降幅在不同剂量方案之间相似。
Dupilumab pharmacokinetics and effect on type 2 biomarkers in children with moderate-to-severe asthma
D. J. Jackson, L. B. Bacharier, W. Phipatanakul, L. Sher, C. Domingo, N. Papadopoulos, et al.
Abstract
BACKGROUND:Type 2 inflammation is common in children with asthma. Dupilumab, a human antibody, blocks the signaling of interleukin -4 and -13, key and central drivers of type 2 inflammation. In the LIBERTY ASTHMA VOYAGE (NCT02948959) study, dupilumab reduced severe asthma exacerbations and improved lung function in children aged 6 to 11 years with uncontrolled, moderate-to-severe asthma.
OBJECTIVE: To assess the pharmacokinetics of dupilumab and type 2 biomarker changes in children with type 2 asthma in VOYAGE.
METHOD:Patients were randomized to dupilumab 100 mg (≤30 kg) or 200 mg (>30 kg) or placebo every 2 weeks for 52 weeks. Dupilumab concentrations and changes in type 2 biomarkers were assessed at each visit.
RESULT:Dupilumab concentrations in serum reached a steady state by week 12, with mean concentrations of 51.2 mg/L and 79.4 mg/L in children receiving dupilumab 100 mg every 2 weeks and 200 mg every 2 weeks, respectively (therapeutic range in adults and adolescents: 29-80 mg/L). Reductions in type 2 biomarkers were comparable between regimens, and greater in patients treated with dupilumab vs placebo. In children treated with dupilumab 100 mg and 200 mg every 2 weeks, the median percent changes (Q1-Q3) from baseline at week 52 were, respectively, -78.6% (-86.3 to -69.80) and -78.6% (-84.9 to -70.1) for serum total immunoglobulin E, -53.6% (-66.4 to -34.6) and -43.7% (-58.6 to -28.5) for thymus and activation-regulated chemokine; -25.7% (-60.0 to 27.6) and -33.3% (-60.6 to 16.6) for blood eosinophils, and -47.7% (-73.8 to 18.9) and -55.6% (-73.6 to -20.0) for fractional exhaled nitric oxide.
CONCLUSION:Weight-tiered dose regimens achieved mean concentrations within the dupilumab therapeutic range. The median decreases in type 2 biomarker levels were similar between dose regimens.
背景：2型炎症在哮喘患儿中很常见。Dupilumab是一种人类抗体，它能阻断白细胞介素-4和-13的信号传导，而白细胞介素-4和-13是2型炎症的关键和核心驱动因素。在LIBERTY ASTHMA VOYAGE (NCT02948959)研究中，Dupilumab减少了6至11岁未控制的中重度哮喘患儿的严重哮喘加重并改善了肺功能。
目的：评估VOYAGE中2型哮喘儿童中Dupilumab的药代动力学和2型生物标志物的变化。
方法：患者被随机分配接受每2周1次dupilumab 100 mg(≤30 kg)或200 mg (30 kg)或安慰剂治疗，共52周。每次访视时评估Dupilumab浓度和2型生物标志物的变化。
结果：血清中Dupilumab的浓度在第12周达到稳态，接受Dupilumab100mg/2周和200mg/2周治疗的儿童的平均浓度分别为51.2mg/L和79.4mg/L（成人和青少年的治疗范围：29-80 mg/L）。不同治疗方案的2型生物标志物降低率相当，接受dupilumab治疗的患者的降低率高于接受安慰剂治疗的患者。在dupilumab 100mg和200mg每2周治疗的患儿中，第52周时血清总免疫球蛋白E的中位数变化百分比(q1～q3)中位数分别为-78.6%(-86.3～-69.80)和-78.6%(-84.9～-70.1)，胸腺和活化调节趋化因子分别为-53.6%(-66.4～-34.6)和-43.7% (-58.6～-28.5);血嗜酸性粒细胞分别为-25.7%(-60.0～27.6)和-33.3%(-60.6～16.6)，呼出气一氧化氮分别为-47.7%(-73.8～18.9)和-55.6%(-73.6～-20.0)。
结论：分级给药方案达到了Dupilumab治疗范围内的平均浓度。2型生物标志物水平的中位降幅在不同剂量方案之间相似。
（中日友好医院呼吸与危重症医学科 李春晓 摘译 林江涛 审校）
（Ann Allergy Asthma Immunol. 2023 Jul;131(1):44-51e4 DOI: 10.1016/j.anai.2023.03.014）
（Ann Allergy Asthma Immunol. 2023 Jul;131(1):44-51e4 DOI: 10.1016/j.anai.2023.03.014）
Dupilumab pharmacokinetics and effect on type 2 biomarkers in children with moderate-to-severe asthma
D. J. Jackson, L. B. Bacharier, W. Phipatanakul, L. Sher, C. Domingo, N. Papadopoulos, et al.
Abstract
BACKGROUND:Type 2 inflammation is common in children with asthma. Dupilumab, a human antibody, blocks the signaling of interleukin -4 and -13, key and central drivers of type 2 inflammation. In the LIBERTY ASTHMA VOYAGE (NCT02948959) study, dupilumab reduced severe asthma exacerbations and improved lung function in children aged 6 to 11 years with uncontrolled, moderate-to-severe asthma.
OBJECTIVE: To assess the pharmacokinetics of dupilumab and type 2 biomarker changes in children with type 2 asthma in VOYAGE.
METHOD:Patients were randomized to dupilumab 100 mg (≤30 kg) or 200 mg (>30 kg) or placebo every 2 weeks for 52 weeks. Dupilumab concentrations and changes in type 2 biomarkers were assessed at each visit.
RESULT:Dupilumab concentrations in serum reached a steady state by week 12, with mean concentrations of 51.2 mg/L and 79.4 mg/L in children receiving dupilumab 100 mg every 2 weeks and 200 mg every 2 weeks, respectively (therapeutic range in adults and adolescents: 29-80 mg/L). Reductions in type 2 biomarkers were comparable between regimens, and greater in patients treated with dupilumab vs placebo. In children treated with dupilumab 100 mg and 200 mg every 2 weeks, the median percent changes (Q1-Q3) from baseline at week 52 were, respectively, -78.6% (-86.3 to -69.80) and -78.6% (-84.9 to -70.1) for serum total immunoglobulin E, -53.6% (-66.4 to -34.6) and -43.7% (-58.6 to -28.5) for thymus and activation-regulated chemokine; -25.7% (-60.0 to 27.6) and -33.3% (-60.6 to 16.6) for blood eosinophils, and -47.7% (-73.8 to 18.9) and -55.6% (-73.6 to -20.0) for fractional exhaled nitric oxide.
CONCLUSION:Weight-tiered dose regimens achieved mean concentrations within the dupilumab therapeutic range. The median decreases in type 2 biomarker levels were similar between dose regimens.
上一篇：
奥马珠单抗可改善阿司匹林所致的呼吸系统疾病急性加重患者的呼吸道外症状
下一篇：
共病导致的治疗效果改变：120项随机对照试验的个体参与者数据荟萃分析
