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

• Published in: Clinical pharmacology and therapeutics 2018-06, Vol.103 (6), p.1020-1028
• Main Authors: Herman, Ann E., Chinn, Leslie W., Kotwal, Shweta G., Murray, Elaine R., Zhao, Rui, Florero, Marilyn, Lin, Alyse, Moein, Anita, Wang, Rena, Bremer, Meire, Kokubu, Serika, Serone, Adrian P., Hanze, Eva L., Viberg, Anders, Morimoto, Alyssa M., Winter, Helen R., Katsumoto, Tamiko R.
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Agammaglobulinaemia Tyrosine Kinase - antagonists & inhibitors; Area Under Curve; Dose-Response Relationship, Drug; Double-Blind Method; Female; Half-Life; Humans; Male; Maximum Tolerated Dose; Metabolic Clearance Rate; Middle Aged; Piperazines - administration & dosage; Piperazines - adverse effects; Piperazines - pharmacokinetics; Piperazines - pharmacology; Protein Kinase Inhibitors - administration & dosage; Protein Kinase Inhibitors - adverse effects; Protein Kinase Inhibitors - pharmacokinetics; Protein Kinase Inhibitors - pharmacology; Pyridones - administration & dosage; Pyridones - adverse effects; Pyridones - pharmacokinetics; Pyridones - pharmacology; Young Adult
• ISSN: 0009-9236; 1532-6535
• DOI: 10.1002/cpt.1056

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.