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Safety, Pharmacokinetics, and Pharmacodynamics in Healthy Volunteers Treated With GDC-0853, a Selective Reversible Bruton's Tyrosine Kinase Inhibitor. Clinical pharmacology and therapeutics Herman, A. E., Chinn, L. W., Kotwal, S. G., Murray, E. R., Zhao, R., Florero, M., Lin, A., Moein, A., Wang, R., Bremer, M., Kokubu, S., Serone, A. P., Hanze, E. L., Viberg, A., Morimoto, A. M., Winter, H. R., Katsumoto, T. R. 2018; 103 (6): 1020-1028

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.

View details for DOI 10.1002/cpt.1056

View details for PubMedID 29484638