A Pharmacometric Approach to Substitute for a Conventional Dose-Finding Study in Rare Diseases: Example of Phase III Dose Selection for Emicizumab in Hemophilia A.
A Pharmacometric Approach to Substitute for a Conventional Dose-Finding Study in Rare Diseases: Example of Phase III Dose Selection for Emicizumab in Hemophilia A.
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DOI：
10.1007/s40262-017-0616-3
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发表时间：
2018-09
影响因子：
4.5
通讯作者：
Kawanishi T
中科院分区：
文献类型：
--
作者：
Yoneyama K;Schmitt C;Kotani N;Levy GG;Kasai R;Iida S;Shima M;Kawanishi T
Emicizumab（ACE 910）是一种模拟活化凝血因子VIII辅因子功能的双特异性抗体。在I-I/II期研究中，emicizumab以0.3、1和3 mg/kg每周一次皮下给药可降低重度血友病A患者的出血频率，无论是否存在凝血因子VIII抑制剂。使用I-I/II期研究数据，进行群体药代动力学和重复事件发生时间（RTTE）建模，以定量描述emicizumab药代动力学与出血频率降低之间的关系。然后进行模拟，以确定至少50%的患者在1年内实现零出血事件的预期最小暴露量，并选择在III期研究中测试的给药方案。RTTE模型充分预测了出血发作随时间的变化，作为emicizumab血浆浓度的函数。模拟结果表明，emicizumab血药浓度≥ 45 μg/mL应导致至少50%的患者1年内无出血事件。该有效暴露量为III期研究选择先前未检测的给药方案（1.5 mg/kg每周一次、3 mg/kg每2周一次和6 mg/kg每4周一次）提供了基础。药理学方法指导emicizumab治疗血友病A的III期剂量选择，而不进行常规剂量探索研究。目前正在进行选定给药方案的III期研究。该案例研究表明，药理学方法可以取代罕见疾病的常规剂量探索研究，并将简化药物开发过程。本文的在线版本（10.1007/s40262-017-0616-3）包含补充材料，可供授权用户使用。
Emicizumab (ACE910) is a bispecific antibody mimicking the cofactor function of activated coagulation factor VIII. In phase I–I/II studies, emicizumab reduced the bleeding frequency in patients with severe hemophilia A, regardless of the presence of factor VIII inhibitors, at once-weekly subcutaneous doses of 0.3, 1, and 3 mg/kg. Using the phase I–I/II study data, population pharmacokinetic and repeated time-to-event (RTTE) modeling were performed to quantitatively characterize the relationship between the pharmacokinetics of emicizumab and reduction in bleeding frequency. Simulations were then performed to identify the minimal exposure expected to achieve zero bleeding events for 1 year in at least 50% of patients and to select the dosing regimens to be tested in phase III studies. The RTTE model adequately predicted the bleeding onset over time as a function of plasma emicizumab concentration. Simulations suggested that plasma emicizumab concentrations of ≥ 45 μg/mL should result in zero bleeding events for 1 year in at least 50% of patients. This efficacious exposure provided the basis for selecting previously untested dosing regimens of 1.5 mg/kg once weekly, 3 mg/kg every 2 weeks, and 6 mg/kg every 4 weeks for phase III studies. A pharmacometric approach guided the phase III dose selection of emicizumab in hemophilia A, without conducting a conventional dose-finding study. Phase III studies with the selected dosing regimens are currently ongoing. This case study indicates that a pharmacometric approach can substitute for a conventional dose-finding study in rare diseases and will streamline the drug development process. The online version of this article (10.1007/s40262-017-0616-3) contains supplementary material, which is available to authorized users.
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影响因子：
20.3
作者：
Konkle, Barbara A.;Stasyshyn, Oleksandra;Abbuehl, Brigitt
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DOI：
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