Takeda Pharmaceuticals International Inc., Cambridge, Massachusetts, USA.
Clin Transl Sci. 2021 May;14(3):820-828. doi: 10.1111/cts.12871. Epub 2021 Mar 2.
Bruton's tyrosine kinase (BTK) is a target for treatment of hematologic malignancies and autoimmune diseases. TAK-020 is a highly selective covalent BTK inhibitor that inhibits both B cell receptor and fragment crystallizable receptor signaling. We assessed the safety/tolerability and pharmacokinetics/pharmacodynamics (PDs) of TAK-020 in healthy subjects. Each cohort of the single-rising dose (n = 72; 9 cohorts) and the multiple-rising dose (n = 48; 6 cohorts) portions of the study comprised six TAK-020-treated and two placebo-treated, subjects aged 18-55 years (inclusive). The PD effects were assessed by measuring BTK occupancy and the inhibition of fragment crystallizable epsilon receptor 1 (FcεRI)-mediated activation of basophils. Overall, treatment-emergent adverse events (TEAEs) were similar to placebo; there were no serious TEAEs or no TEAEs leading to discontinuation. TAK-020 was rapidly absorbed (median time to maximum plasma concentration (T ) 45-60 minutes) with a half-life of ~ 3-9 hours at doses ≥ 2.5 mg. TAK-020 exposure was generally dose proportional for single doses ≤ 70 mg and after multiple doses of ≤ 60 mg once daily. Target occupancy was dose dependent, with doses ≥ 2.5 mg yielding maximum and sustained occupancy > 70% for > 96 hours. Single doses ≥ 4.4 mg reduced FcεRI-mediated activation of basophils by > 80% and comparable inhibition was observed with daily dosing ≥3.75 mg for 9 days. Inhibition persisted for 24-72 hours postdose and the duration generally increased with dose. TAK-020 was generally well-tolerated in healthy subjects after single and multiple doses and demonstrated target engagement and pathway modulation. The PD effects outlasted drug exposures, as expected for covalent inhibition of BTK.
布鲁顿酪氨酸激酶（BTK）是治疗血液系统恶性肿瘤和自身免疫性疾病的靶点。TAK-020 是一种高度选择性的共价 BTK 抑制剂，可抑制 B 细胞受体和片段结晶受体信号。我们评估了 TAK-020 在健康受试者中的安全性/耐受性和药代动力学/药效学（PDs）。研究的单剂量递增（n=72；9 个队列）和多剂量递增（n=48；6 个队列）部分的每个队列均包含 6 个 TAK-020 治疗组和 2 个安慰剂治疗组，年龄在 18-55 岁（含）之间。通过测量 BTK 占有率和片段结晶受体 epsilon 1（FcεRI）介导的嗜碱性粒细胞激活的抑制作用来评估 PD 效应。总体而言，治疗后出现的不良事件（TEAEs）与安慰剂相似；没有严重的 TEAEs 或导致停药的 TEAEs。TAK-020 吸收迅速（最大血浆浓度（T ）中位数时间为 45-60 分钟），剂量≥2.5mg 时半衰期约为 3-9 小时。在单剂量≤70mg 和多剂量≤60mg 每日一次时，TAK-020 暴露量通常与剂量成正比。目标占有率与剂量有关，剂量≥2.5mg 可产生>70%的最大和持续占有率>96 小时。单剂量≥4.4mg 可使 FcεRI 介导的嗜碱性粒细胞激活降低>80%，每日≥3.75mg 连续给药 9 天可观察到类似的抑制作用。抑制作用持续 24-72 小时，随着剂量的增加，持续时间通常会延长。TAK-020 在健康受试者中单剂量和多剂量后通常具有良好的耐受性，并表现出靶标结合和通路调节。PD 效应持续时间超过药物暴露时间，这与 BTK 的共价抑制作用一致。
