Background/Purpose: GS-4059 is a covalent inhibitor of Bruton’s Tyrosine Kinase (BTK) under development for the treatment of rheumatoid arthritis (RA) and oncology. This work aimed at characterizing the in vitro and in vivo binding kinetics of GS-4059 and, using pharmacokinetic-pharmacodynamic modeling, to explore the relationship between dose and BTK occupancy to provide a framework for dose selection in clinical studies.

Methods:  In vitro, BTK inactivation kinetics of GS-4059 and two other irreversible BTK inhibitors, CC-292 (Cellgene) and ACP-196 (Acerta), was characterized using the Omnia Kinase assay, a highly sensitive fluorescence-based assay that allows for continuous monitoring of BTK activity. Ex vivo BTK binding by GS-4059 was investigated in samples from healthy volunteers who received a single 100 mg or multiple once daily 20 mg oral doses of GS-4059. Free and total (free + drug bound) BTK in peripheral blood mononuclear cells (PBMCs) was measured. A pharmacokinetic-pharmacodynamic (PKPD) model (NONMEM v.7.3) incorporating both BTK inactivation and turnover in PBMCs was developed. BTK occupancy in both PBMCs and splenocytes after multiple ascending daily doses (1.25 – 160 mg) were simulated based on model derived BTK binding kinetics to predict the optimal dose(s) to explore in future studies.

Results: All three compounds exhibited efficient BTK inactivation in vitro with comparable time-dependent inactivation rates over affinity constant ratios (k_inact/K_I: 86 – 133 µM^-1*h^-1). Significant BTK occupancy was observed after single 100 mg and multiple once daily 20 mg GS-4059 dosing and this occupancy persisted following GS-4059 washout. The PKPD model estimated in vivo population k_inact/K_I (69 µM^-1*h^-1) was in agreement with the in vitro data. The BTK degradation half-life in PBMCs was estimated to be 64 h (k_deg value of 0.011 h^-1) providing an explanation for the significant persistence of BTK occupancy following drug washout. Simulations conducted to explore dose (range of 1.25 – 160 mg) suggested that once daily 10 mg GS-4059 provides >80% BTK occupancy in PBMCs over a 24 h period at steady-state; higher doses may be needed to obtain comparable occupancy in the splenocytes.

Conclusion: This analysis provides a mechanistic understanding of in vivo time- and concentration-dependent BTK inactivation and presents a valuable tool in guiding GS-4059 dose selection for RA and oncology patients. The results in this abstract are planned to be presented in part at the American Conference on Pharmacometrics in Bellevue, WA, October 23^rd to October 26^th, 2016, and published in the conference proceedings (abstract number T.B.D.)

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/pharmacokinetic-pharmacodynamic-analysis-of-gs-4059-mediated-brutons-tyrosine-kinase-inhibition/