Clinical Pharmacology, Drug Metabolism and Pharmacokinetics, MedImmune, Cambridge, UK.
Department of Pharmaceutical Biosciences, Faculty of Pharmacy, Uppsala University, Uppsala, Sweden.
Clin Pharmacol Ther. 2018 May;103(5):826-835. doi: 10.1002/cpt.803. Epub 2017 Sep 28.
Interleukin (IL)-13 is involved in the pathogenesis of some types of asthma. Tralokinumab is a human immunoglobulin G monoclonal antibody that specifically binds to IL-13. Two placebo-controlled phase II studies (phase IIa, NCT00873860 and phase IIb, NCT01402986) have been conducted in which tralokinumab was administered subcutaneously. This investigation aimed to characterize tralokinumab's dose-exposure-response (forced expiratory volume in 1 s (FEV )) relationship in patients with asthma and to predict the most appropriate dose for phase III. An integrated population pharmacokinetic-pharmacodynamic (PK/PD) modeling analysis was required for phase III dose selection, due to differing phase II patient populations, designs, and regimens. Analysis of combined datasets enabled the identification of tralokinumab's dose-exposure-FEV response relationship in patients with asthma. Near-maximal FEV increase was predicted at a dose of 300 mg SC once every 2 weeks (Q2W). This dose was chosen for tralokinumab in the phase III clinical development program for treatment of severe, uncontrolled asthma.
白细胞介素（IL）-13 参与了某些类型哮喘的发病机制。特利鲁单抗是一种人源化 IgG 单克隆抗体，可特异性结合 IL-13。两项安慰剂对照的 II 期研究（IIa 期，NCT00873860 和 IIb 期，NCT01402986）已经进行，特利鲁单抗通过皮下给药。本研究旨在描述特利鲁单抗在哮喘患者中的剂量-暴露-反应（1 秒用力呼气量（FEV ））关系，并预测 III 期最适宜的剂量。由于 II 期患者人群、设计和方案不同，需要进行综合群体药代动力学-药效学（PK/PD）模型分析，以选择 III 期剂量。对合并数据集的分析可确定特利鲁单抗在哮喘患者中的剂量-暴露-FEV 反应关系。预测每 2 周（Q2W）皮下注射 300mg 特利鲁单抗可使 FEV 接近最大程度增加。在治疗重度、未控制的哮喘的 III 期临床开发项目中，选择了该剂量用于特利鲁单抗。
