THU0117 PHARMACOKINETICS AND SHORT-TERM SAFETY OF FILGOTINIB, A SELECTIVE JANUS KINASE 1 INHIBITOR, IN SUBJECTS WITH MODERATE HEPATIC IMPAIRMENT. (June 2019)

• Record Type: Journal Article
• Authors: Anderson, Kacey; Zheng, Hao; Medzihradsky, Oliver; Yizhao, LI; Qin, Ann; Kearney, Brian; Mathias, Anita
• Is Part Of: Annals of the rheumatic diseases. Volume 78(2019)Supplement 2
• Page Start: 331
• Page End: 331
• Publication Date: 2019-06
• Subjects: Rheumatism -- Periodicals; 616.723005
• DOI: 10.1136/annrheumdis-2019-eular.2325
• Languages: English
• ISSNs: 0003-4967

Abstract

Abstract : 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.