Indications
Filgotinib is indicated for the management of active moderate to severe rheumatoid arthritis, either as a monotherapy or in combination with methotrexate. It is particularly reserved for patients who cannot tolerate or have not responded adequately to one or more disease-modifying anti-rheumatic drugs (DMARDs). Additionally, filgotinib is approved for the treatment of moderate to severely active ulcerative colitis in adult patients who have experienced an insufficient response, loss of response, or intolerance to conventional therapies or biologic agents.
Pharmacodynamics
Filgotinib serves as a targeted Janus kinase (JAK) 1 inhibitor and effectively modulates pro-inflammatory cytokine signaling. It achieves this by inhibiting the IL-6 induced phosphorylation of STAT1, resulting in reduced inflammation. Moreover, the treatment with filgotinib has been associated with a decrease in serum C-reactive protein levels, further highlighting its anti-inflammatory properties.
Absorption
Following oral administration, filgotinib is quickly absorbed, reaching median peak plasma concentrations approximately 2 to 3 hours post-dose. For its major metabolite, GS-829845, peak concentrations are reached around 5 hours post-dose. Steady-state levels are typically achieved within 2 to 3 days for filgotinib, and 4 days for GS-829845. Importantly, food intake does not significantly impact the absorption of filgotinib, making it convenient for administration with or without meals. After repeated dosing of 200 mg, the maximum concentration (Cmax) and area under the curve (AUCτ) values for filgotinib were observed at 2.15 µg/mL and 6.77 µg·h/mL, respectively. For the metabolite GS-829845, the Cmax was 4.43 µg/mL and the AUCτ was 83.2 µg·h/mL.
Metabolism
The metabolism of filgotinib primarily involves carboxylesterase enzymes, with the carboxylesterase 2 (CES2) isoform playing a major role in converting filgotinib to its primary metabolite GS-829845. While carboxylesterase 1 (CES1) has a lesser role in this metabolic pathway, in vitro studies suggest CES1 can partially compensate if CES2 becomes saturated. GS-829845 remains the only major circulating metabolite identified thus far.
Mechanism of Action
Filgotinib functions as a selective inhibitor of the Janus kinase 1 (JAK1), playing a crucial role in modulating the JAK-signal transducer and activator of transcription (STAT) pathway, which is significantly involved in inflammatory processes. Among the four JAK enzymes-JAK1, JAK2, JAK3, and tyrosine kinase 2-JAK1 primarily facilitates inflammatory cytokine signaling, whereas JAK2 and JAK3 are critical to hematologic and immune functions. Filgotinib demonstrates remarkable selectivity by being nearly 30-fold more specific for JAK1 over JAK2. This specificity becomes clinically relevant in conditions such as rheumatoid arthritis (RA), where the JAK-STAT pathway is excessively active, driving disease progression through increased levels of matrix metalloproteinases and reduced apoptosis in affected synovial tissues. By inhibiting JAK1 phosphorylation, Filgotinib effectively blocks STAT activation, resulting in decreased proinflammatory cytokine signaling and helping to control the inflammatory responses associated with RA.
