qPharmetra, 506 Grant Forest Lane, Cary, NC, 27519, USA.
Clinical Pharmacology, Roche Pharma Research and Early Development, Roche Innovation Center, Basel, Switzerland.
Clin Pharmacokinet. 2021 Jul;60(7):931-941. doi: 10.1007/s40262-021-01006-0. Epub 2021 Mar 12.
Emicizumab is a monoclonal antibody that bridges activated coagulation factor IX and factor X to restore effective hemostasis in persons with hemophilia A. It is indicated for routine prophylaxis of bleeding episodes in persons with hemophilia A. The aim of the present study is to describe the exposure-response relationship between emicizumab concentrations and bleeding frequency, and to confirm adequate bleeding control of the investigated dosing regimens 1.5 mg/kg once weekly, 3 mg/kg every 2 weeks, and 6 mg/kg every 4 weeks.
Treated bleeding events were pooled from 445 persons with hemophilia A with and without inhibitors against factor VIII, participating in six clinical studies. Emicizumab concentrations were predicted using a previously developed population pharmacokinetic model. A count model was used to quantify the exposure-response relationship. These models were used to illustrate the relationship between emicizumab concentrations and cumulative count of bleeding over 1 year (annualized bleeding rate).
The final exposure-response model, based on a generalized Poisson distribution and an inhibitory E relationship, adequately describes the relationship between daily emicizumab concentrations and daily bleed frequency. A significant effect of factor VIII prophylaxis among persons with hemophilia A without inhibitors was found. Annualized bleeding rate simulations show that the three emicizumab dosing regimens maintain the concentrations close to the plateau of the effect. At the average steady-state concentration across all regimens (53.5 µg/mL), the predicted mean annualized bleeding rate is 1.28, corresponding to a 94.0% reduction from baseline.
These results confirm that average emicizumab concentrations achieved with all three emicizumab dosing regimens provide adequate bleeding control.
依库珠单抗是一种单克隆抗体，可桥接激活的凝血因子 IX 和因子 X，以恢复血友病 A 患者的有效止血。它被批准用于血友病 A 患者常规预防出血发作。本研究的目的是描述依库珠单抗浓度与出血频率之间的暴露-反应关系，并确认所研究的给药方案 1.5mg/kg 每周一次、3mg/kg 每两周一次和 6mg/kg 每四周一次能够充分控制出血。
来自 445 名有或无VIII 因子抑制剂的血友病 A 患者的治疗性出血事件被汇总，这些患者参加了六项临床研究。使用先前开发的群体药代动力学模型预测依库珠单抗浓度。计数模型用于量化暴露-反应关系。这些模型用于说明依库珠单抗浓度与 1 年内累积出血计数（年化出血率）之间的关系。
基于广义泊松分布和抑制 E 关系的最终暴露-反应模型充分描述了依库珠单抗浓度与每日出血频率之间的关系。在无 VIII 因子抑制剂的血友病 A 患者中发现了因子 VIII 预防的显著效果。年化出血率模拟表明，三种依库珠单抗给药方案可使浓度维持在接近效应平台的水平。在所有方案的平均稳态浓度（53.5μg/mL）下，预测的平均年化出血率为 1.28，与基线相比降低了 94.0%。
这些结果证实，所有三种依库珠单抗给药方案达到的平均依库珠单抗浓度可提供充分的出血控制。
