LAUSR

Background Filgotinib (FIL) is an oral selective Janus kinase 1 (JAK1) inhibitor being developed to treat inflammatory diseases. Objectives This phase 1 study evaluated the pharmacokinetics (PK) and short-term safety of FIL in subjects with hepatic impairment (HI) to guide safe and appropriate dosing in the presence of this comorbidity. Methods This study enrolled 20 subjects: 10 with moderate (Child-Turcotte-Pugh-B) HI and 10 healthy controls. All were matched for age, sex, and body mass index and received a single oral dose of FIL 100 mg followed by intensive plasma PK sampling over 120 hours. Plasma concentrations of FIL and its primary circulating metabolite were measured by validated LC-MS/MS methods; plasma protein binding was also evaluated. A parametric analysis of variance was applied to the natural logarithmic transformation of PK parameters (AUC and Cmax) for FIL and its metabolite. Geometric least squares means (GLSM) ratios and 90% confidence intervals (CIs) of PK parameters were evaluated in subjects with moderate HI relative to controls, with clinically relevant exposure change defined as ≥2-fold for FIL or its metabolite. Safety endpoints consisted of the incidence of adverse events (AEs), laboratory abnormalities, and vital sign and electrocardiogram changes monitored through day 15. Results All subjects completed the protocol-specified dosing and assessments. FIL and metabolite AUCs were increased by 1.6- and 1.2-fold, respectively, in subjects with moderate HI compared to controls. Protein bindings of FIL and its metabolite (fu: 41%–44% and 55%–61%, respectively) were unchanged in subjects with moderate HI. FIL was well tolerated, with no serious AEs reported. All treatment-emergent AEs were Grade 1 in severity. Serum and plasma markers did not show evidence of treatment-emergent hepatotoxicity or worsened liver function and were consistent with the use of FIL in a population with moderate HI. Conclusion In the setting of moderate HI, a single oral dose of FIL 100 mg was well tolerated. FIL can be administered without predefined dose adjustment to patients with mild to moderate HI. Disclosure of Interests Kacey Anderson Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Hao Zheng Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Oliver Medzihradsky Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Yizhao Li Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Ann Qin Employee of: Gilead Sciences, Inc., Brian Kearney Employee of: Gilead Sciences, Inc., Anita Mathias Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc.