Background/Purpose: Filgotinib is an oral, selective Janus kinase 1 (JAK1) inhibitor combining clinical efficacy and a rapid onset of action with a good safety profile in patients with rheumatoid arthritis (RA).  While people of any age can be affected by RA, the disease is common in the elderly. Age-related processes may have an impact on drug metabolism and pharmacokinetics (PK), among others from an age-related decline in enzymes activity and glomerular filtration rate (GFR). Given that metabolism followed by renal excretion is the main routes of elimination for filgotinib and its active metabolite, the impact of age as well as renal impairment on PK and safety of filgotinib was studied./Assess the PK, tolerability and safety of filgotinib in elderly subjects and in subjects with various degrees of renal impairment.

Methods: The effect of age on filgotinib PK was assessed in a single-center Phase 1 study with two groups (N=10 per group) of  healthy elderly subjects (65-74 years and ≥75 years) and one group of younger healthy subjects (40-50 years). In a second single-center Phase 1 study, subjects with mild (GFR: 60-89 mL/min/1.73m²; n=6), moderate (GFR: 30-59 mL/min/1.73m²; n=6) and severe (GFR: 15-29 mL/min/1.73m²; n=3) renal impairment and one group with normal renal function (GFR: ≥ 90 mL/min/1.73m²; n=9) were included to investigate the effect of renal impairment on filgotinib PK. In both studies, male and female subjects received once daily 100 mg filgotinib orally for 10 days. The PK of filgotinib and its main metabolite were evaluated. Standard safety assessments were performed throughout the studies.

Results: At steady state, filgotinib plasma exposure was moderately increased (1.4-fold) in the oldest subjects (≥75y) compared to younger subjects. Neither the apparent terminal elimination half-life nor the amounts of filgotinib excreted unchanged in urine were impacted by the age. An exposure increase was also observed for its main metabolite, suggesting no impact of age on filgotinib’ drug metabolism. Renal clearance of filgotinib and its main active metabolite decreased with the degree of renal impairment leading to 1.5- and 2.7-fold increase in exposure in subjects with severe renal impairment, respectively. Filgotinib was generally safe and well tolerated in elderly and in subjects with renal impairment. There were no deaths or serious adverse events reported. Most of the treatment emergent adverse advents (TEAEs) were mild. Safety profiles in elderly and in subjects with renal impairment were similar to young heathy subjects.

Conclusion: Higher age and mild to moderate impairment of renal function has a limited impact on the PK of filgotinib. In severe renal impairment, the exposure to filgotinib’s active metabolite is elevated, consistent with its renal elimination pathway. This was not associated with safety signals in these Phase 1 studies.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/influence-of-age-and-renal-impairment-on-pharmacokinetics-of-filgotinib-glpg0634-a-selective-jak1-inhibitor/