Global Drug Discovery, Novo Nordisk A/S, Måløv, Denmark.
Global Development, Novo Nordisk A/S, Bagsvaerd, Denmark.
J Thromb Haemost. 2021 Jul;19(7):1687-1696. doi: 10.1111/jth.15323. Epub 2021 May 6.
The anti-tissue factor plasma inhibitor monoclonal antibody concizumab is under clinical investigation for subcutaneous prophylaxis of hemophilia A/B (HA/HB) with or without inhibitors. Breakthrough bleeds while on concizumab prophylaxis may be treated with bypassing agents (recombinant activated factor VIIa [rFVIIa] and activated prothrombin complex concentrate [APCC]), or with factor VIII (FVIII) or factor IX (FIX).
To evaluate the effect of combining concizumab with rFVIIa, APCC, rFVIII, and rFIX on thrombin generation (TG) potential.
Pooled HA plasma was spiked in vitro with concizumab alone or together with rFVIIa, APCC, or rFVIII. rFVIIa, APCC, and rFVIII were added ex vivo to plasma from HA patients receiving concizumab prophylaxis. Pooled HB plasma was spiked with concizumab alone or together with rFIX. TG potential was measured after initiation with tissue factor.
Concizumab increased thrombin peak in a concentration-dependent manner. Adding rFVIIa, APCC, rFVIII, or rFIX caused a further increase in thrombin peak. The effects of concizumab and rFVIIa, APCC, rFVIII, or rFIX were mainly additive, with no or up to maximally ~25% extra effect caused by drug--drug interaction. No strong synergistic effects were observed upon combining concizumab with rFVIIa, APCC, rFVIII, or rFIX. The thrombin peak obtained with 0.5 IU/ml rFVIII or rFIX in the presence of concizumab was on occasion slightly higher, but mostly comparable to the thrombin peak with 1 IU/ml rFVIII or rFIX in the absence of concizumab.
rFVIIa, APCC, rFVIII, and rFIX enhanced plasma TG potential in the presence of concizumab. Dose levels of concomitant use should be adjusted accordingly to balance potential safety concerns while maintaining the necessary hemostatic effect. Please see the video in the Supplementary Material for an animated summary of the data presented.
抗组织因子血浆抑制剂单克隆抗体 concizumab 正在进行临床试验，以皮下预防有或无抑制剂的血友病 A/B（HA/HB）。在 concizumab 预防过程中出现突破性出血时，可使用旁路制剂（重组活化因子 VIIa [rFVIIa] 和活化的凝血酶原复合物浓缩物 [APCC]）或因子 VIII（FVIII）或因子 IX（FIX）进行治疗。
评估 concizumab 与 rFVIIa、APCC、rFVIII 和 rFIX 联合使用对凝血酶生成（TG）潜力的影响。
将 HA 血浆体外加入 concizumab 单独或与 rFVIIa、APCC 或 rFVIII 一起进行加标。rFVIIa、APCC 和 rFVIII 被添加到接受 concizumab 预防的 HA 患者的血浆中进行离体添加。HB 血浆单独加入 concizumab 或与 rFIX 一起进行加标。在组织因子启动后测量 TG 潜力。
concizumab 以浓度依赖的方式增加凝血酶峰。添加 rFVIIa、APCC、rFVIII 或 rFIX 会导致凝血酶峰进一步增加。concizumab 和 rFVIIa、APCC、rFVIII 或 rFIX 的作用主要是相加的，药物-药物相互作用没有或最多增加 25%的额外作用。在 concizumab 与 rFVIIa、APCC、rFVIII 或 rFIX 联合使用时，未观察到强烈的协同作用。在 concizumab 存在的情况下，使用 0.5 IU/ml rFVIII 或 rFIX 获得的凝血酶峰偶尔会略高，但与 concizumab 不存在时使用 1 IU/ml rFVIII 或 rFIX 获得的凝血酶峰基本相当。
rFVIIa、APCC、rFVIII 和 rFIX 增强了 concizumab 存在时的血浆 TG 潜力。应相应调整联合使用的剂量水平，以平衡潜在的安全性问题，同时保持必要的止血效果。请观看补充材料中的视频，以获取所呈现数据的动画摘要。
