药代动力学
药效学
药理学
加药
医学
布鲁顿酪氨酸激酶
类风湿性关节炎
安慰剂
不利影响
内科学
酪氨酸激酶
受体
病理
替代医学
作者
Ann Herman,Leslie W. Chinn,Shweta G. Kotwal,Elaine R. Murray,Rui Zhao,Marilyn Florero,Alyse Lin,Anita Moein,Rena Wang,Meire Bremer,Serika Kokubu,Adrian Serone,Eva Hanze,Anders Viberg,Alyssa Morimoto,Helen Winter,Tamiko R. Katsumoto
摘要
GDC‐0853 is a small molecule inhibitor of Bruton's tyrosine kinase (BTK) that is highly selective and noncovalent, leading to reversible binding. In double‐blind, randomized, and placebo‐controlled phase I healthy volunteer studies, GDC‐0853 was well tolerated, with no dose‐limiting adverse events (AEs) or serious AEs. The maximum tolerated dose was not reached during dose escalation (≤600 mg, single ascending dose (SAD) study; ≤250 mg twice daily (b.i.d.) and ≤500 mg once daily, 14‐day multiple ascending dose (MAD) study). Plasma concentrations peaked 1–3 hours after oral administration and declined thereafter, with a steady‐state half‐life ranging from 4.2–9.9 hours. Independent assays demonstrated dose‐dependent BTK target engagement. Based on pharmacokinetic/pharmacodynamic (PK/PD) simulations, a once‐daily dosing regimen (e.g., 100 mg, q.d.) is expected to maintain a high level of BTK inhibition over the dosing interval. Taken together, the safety and PK/PD data support GDC‐0853 evaluation in rheumatoid arthritis, lupus, and other autoimmune or inflammatory indications.
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