Pharmacokinetics, Pharmacodynamics, and Safety of Subcutaneous and Intravenous Garadacimab Following Single-Dose Administration in Healthy Japanese and White Adults

Fiona Glassman PhD, John-Philip Lawo PhD, Mihai Alexandru Bica MD, MPH, Anthony Roberts PhD, Dipti Pawaskar PhD, Hideto Akama MD, PhD, Meena Jain MD, Summer Goodson PhD
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Abstract

Garadacimab, an activated factor XII (FXIIa) inhibitor monoclonal antibody, is being evaluated for the long-term prophylaxis of hereditary angioedema. Here, we report the results from a two-part, phase 1, open-label, single ascending dose study assessing the pharmacokinetics (PK), pharmacodynamics, safety, and tolerability after subcutaneous (SC) and intravenous (IV) administration of garadacimab in healthy Japanese and White participants. Part 1 assessed garadacimab PK after SC administration of a 200 mg dose in weight-matched White and Japanese participants, and 600 mg dose in Japanese participants. Part 2 assessed 3 and 10 mg/kg IV doses in Japanese participants. Follow-up for safety was over 84 days post-dose. Overall, 37 participants received garadacimab dosing and 36 completed the study, with one participant lost to follow-up. Following SC administration, time to maximum plasma concentration (tmax) occurred at 7 days post-dose, and garadacimab exposure, based on maximum plasma concentration (Cmax) and area under the plasma concentration–time curve (AUC), increased less than 3-fold when tripling the dose. PK was comparable between Japanese and White participants, with geometric mean ratios for Cmax and AUC close to 100%. Following IV administration, tmax occurred at the end of infusion, and garadacimab exposure increased in a dose-proportional manner. Inhibition of FXIIa-mediated kallikrein activity versus baseline was observed in all participants receiving the SC and IV doses. No anti-drug antibodies against garadacimab were reported. Consistent with pivotal phase 3 (VANGUARD) outcomes, no safety concerns and no difference in the safety profile of garadacimab were observed between healthy Japanese and White participants.

Abstract Image

健康日本人和白人成人单剂量皮下注射和静脉注射加拉达西单抗的药代动力学、药效学和安全性
加拉地单抗是一种活化因子 XII (FXIIa) 抑制剂单克隆抗体,目前正被评估用于遗传性血管性水肿的长期预防。在此,我们报告了一项由两部分组成的一期开放标签单剂量递增研究的结果,该研究评估了健康的日本人和白人患者皮下注射(SC)和静脉注射(IV)加拉达西单抗后的药代动力学(PK)、药效学、安全性和耐受性。第 1 部分评估了体重匹配的白人和日本参试者皮下注射 200 毫克剂量和日本参试者注射 600 毫克剂量后的加拉达单抗 PK。第二部分评估了日本参试者3毫克/千克和10毫克/千克静脉注射剂量。安全性随访时间为给药后 84 天。共有37人接受了加拉达西单抗给药,36人完成了研究,1人失去了随访机会。经皮下注射给药后,达到最大血浆浓度(tmax)的时间为给药后7天,根据最大血浆浓度(Cmax)和血浆浓度-时间曲线下面积(AUC)计算,当剂量增加两倍时,加拉达西单抗的暴露量增加不到3倍。日本人和白人参与者的 PK 值相当,Cmax 和 AUC 的几何平均比接近 100%。静脉给药后,tmax 出现在输注结束时,加拉达西单抗的暴露量按剂量比例增加。与基线相比,所有接受皮下注射和静脉注射的参试者都观察到了FXIIa介导的凯利克瑞林活性抑制作用。未发现针对加拉达西单抗的抗药性抗体。与关键的第三阶段(VANGUARD)结果一致,在健康的日本人和白人参试者之间没有观察到安全性问题,加拉达西单抗的安全性也没有差异。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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