Safety, Pharmacokinetics, and Pharmacodynamics in Healthy Volunteers Treated With GDC-0853, a Selective Reversible Bruton's Tyrosine Kinase Inhibitor

Clinical Pharmacology and Therapeutics
Ann E HermanTamiko R Katsumoto

Abstract

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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Citations

Jul 18, 2018·Current Opinion in Allergy and Clinical Immunology·Emek Kocatürk, Torsten Zuberbier
Aug 4, 2019·Clinical Pharmacology and Therapeutics·Nicholas S JonesLeslie W Chinn
Jun 7, 2019·Allergy, Asthma & Immunology Research·Taek Ki Min, Sarbjit S Saini
Aug 3, 2019·The Journal of Pharmacology and Experimental Therapeutics·Nicholas Steven JonesLeslie Chinn
Nov 15, 2019·HemaSphere·Deyan Y YosifovDaniel Mertens
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