Population Pharmacokinetics and Exposure-Response Analysis of Benralizumab in Chinese Adults, Adolescents, and Pediatric Participants with Severe Eosinophilic Asthma.
Yuwen Jin, Benjamin Guiastrennec, Miriam Stuke, Yuhui Yao, Yajuan Zhang, Peter Barker, Maria Jison, Robert C Penland, Junjie Ding, Pradeep B Lukka
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Abstract
Introduction: Benralizumab is approved as add-on subcutaneous therapy in patients aged ≥ 12 years with severe eosinophilic asthma in > 80 countries, including mainland China.
Objective: The study objective was to update benralizumab population pharmacokinetic (popPK) and exposure-response (ER) models in Chinese, Asian (including Chinese), and non-Asian participants.
Methods: Benralizumab popPK/ER models for asthma exacerbation rate and pre-bronchodilator forced expiratory volume in 1 second (FEV1) were updated for three benralizumab trials involving Chinese, Asian (including Chinese), and non-Asian participants. The ER analysis examined correlations between pharmacokinetic quartiles and annual asthma exacerbation rate (AAER) ratios with simulations comparing predicted clinical outcomes.
Results: Updated data included 17,465 benralizumab concentrations (n = 2855). The updated model predicted a slight, and not clinically relevant, increase (< 14%) in benralizumab exposure for Chinese versus non-Asian adults. Median exposure increased in Chinese adolescents versus adults owing to body weight differences, but no dose adjustment was needed. Chinese children weighing < 35 kg receiving a 10 mg dose had similar exposure to those weighing ≥ 35 kg receiving a 30 mg dose. In Chinese versus non-Chinese participants, there was no trend concerning AAER ratios across different trough concentration quartiles; the maximal treatment effect significantly increased (+127%; p < 0.001), and there was no statistically significant effect on pre-bronchodilator FEV1. Steady-state simulations showed lower predicted AAER ratios in Chinese (0.38; 95% confidence interval [CI] 0.32-0.45) than in non-Chinese adults (0.64; 95% CI 0.60-0.71), and no relevant differences between Chinese adults (0.46; 95% CI 0.38-0.54) and adolescents (0.46; 95% CI 0.37-0.55).
Conclusion: The benralizumab popPK/ER models showed good predictive performance across Chinese demographics.
Benralizumab在bb80个国家（包括中国大陆）被批准作为12岁以上严重嗜酸性粒细胞性哮喘患者的附加皮下治疗。目的：研究目的是更新中国、亚洲（包括中国人）和非亚洲参与者的苯那利珠单抗群体药代动力学（popPK）和暴露反应（ER）模型。方法：更新了三个Benralizumab试验的哮喘加重率和支气管扩张剂前1秒用力呼气量（FEV1）的Benralizumab popPK/ER模型，涉及中国人、亚洲人（包括中国人）和非亚洲人。ER分析检查了药代动力学四分位数与年度哮喘加重率（AAER）比率之间的相关性，并模拟比较了预测的临床结果。结果：更新的数据包括17,465个benralizumab浓度（n = 2855）。更新后的模型预测了轻微的，与临床无关的增加(1)。稳态模拟结果显示，中国人的aer预测值较低(0.38；95%可信区间[CI] 0.32-0.45)高于非华裔成年人(0.64；95% CI 0.60-0.71)，中国成年人之间无相关差异(0.46；95% CI 0.38-0.54)和青少年(0.46；95% ci 0.37-0.55)。结论：benralizumab popPK/ER模型在中国人口统计学中具有良好的预测性能。试验注册号：NCT03186209。试验注册日期：2017年7月6日。
期刊介绍：
Clinical Pharmacokinetics promotes the continuing development of clinical pharmacokinetics and pharmacodynamics for the improvement of drug therapy, and for furthering postgraduate education in clinical pharmacology and therapeutics.
Pharmacokinetics, the study of drug disposition in the body, is an integral part of drug development and rational use. Knowledge and application of pharmacokinetic principles leads to accelerated drug development, cost effective drug use and a reduced frequency of adverse effects and drug interactions.
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