Filgotinib: A Clinical Pharmacology Review

Abstract

Filgotinib (GS-6034, formerly GLPG0634; Jyseleca ® ) is an oral, preferential Janus kinase (JAK)-1 inhibitor. Preferential inhibition of JAK1 modulates a subset of proinflammatory cytokines within the JAK–signal transducer and activator of transcription pathway, which differ from those inhibited by JAK2 or JAK3. Filgotinib is absorbed extensively and rapidly after oral dosing and is metabolized by carboxylesterase isoform 2 to form its primary active metabolite, GS-829845. The primary metabolite has a similar JAK1 selectivity profile but reduced activity (by 10-fold) and increased systemic exposure (approximately 16- to 20-fold) compared with the parent compound. Both the parent and the metabolite demonstrate low binding to plasma proteins in humans (< 60%). Systemic exposures of filgotinib and its primary metabolite increase dose proportionally over a 50- to 200-mg once-daily dose range. Food does not affect the pharmacokinetics of filgotinib. Consistent with their terminal elimination half-lives (4.9–10.7 h for filgotinib and 19.6–27.3 h for the primary metabolite), steady state in plasma is reached by day 2 for filgotinib and day 4 for its metabolite. Filgotinib is mainly eliminated in the urine as the metabolite (> 80%). Intrinsic factors such as age, sex, race, mild renal impairment, and mild-to-moderate hepatic impairment have either no or minimal impact on the pharmacokinetics of filgotinib and its primary metabolite. Filgotinib has a low drug–drug interaction potential, without clinically significant interactions with commonly coadministered medications in patients with inflammatory diseases. Both filgotinib and its primary metabolite are substrates of P-glycoprotein (P-gp); however, coadministration with P-gp inhibitors and inducers does not affect filgotinib pharmacokinetics sufficiently to warrant dose adjustment. Neither filgotinib nor its primary metabolite affect the corrected QT interval (calculated using Fridericia’s correction formula). Filgotinib is approved for the treatment of rheumatoid arthritis and ulcerative colitis in Europe, the UK, and Japan.

Insight into Janus kinases specificity: From molecular architecture to cancer therapeutics

“…Currently, there are mainly 13 approved JAKi (Figure 3D) in the market: Ruxolitinib (1), [86][87][88][89][90][91] Tofacitinib (2), [92][93][94][95][96][97] Oclacitinib (for dogs), [98][99][100] Delgocitinib (3), [101][102][103][104] Baricitinib (4), [105][106][107][108] Upadacitinib (5), [109][110][111][112][113] Fedratinib (6), [114][115][116][117][118][119] Filgotinib (7), 68,[120][121][122][123] Abrocitinib (8), [124][125][126][127] Deucravacitinib (9), [128][129][130][131] Ritlecitinib (10), [132]…”

“…Currently, there are mainly 13 approved JAKi (Figure 3D) in the market: Ruxolitinib ( 1 ), 86–91 Tofacitinib ( 2 ), 92–97 Oclacitinib (for dogs), 98–100 Delgocitinib ( 3 ), 101–104 Baricitinib ( 4 ), 105–108 Upadacitinib ( 5 ), 109–113 Fedratinib ( 6 ), 114–119 Filgotinib ( 7 ), 68,120–123 Abrocitinib ( 8 ), 124–127 Deucravacitinib ( 9 ), 128–131 Ritlecitinib ( 10 ), 132–137 Pacritinib ( 11 ) 138–140 and Momelotinib ( 12 ) 141–144 . These drugs are used to treat various conditions including myelofibrosis, bone marrow cancer, rheumatoid arthritis (RA) and psoriasis.…”

Review article: Risk of cardiovascular events in patients with inflammatory bowel disease receiving small molecule drugs

“…62 Filgotinib is another selective JAK1 inhibitor, as it has more than fivefold greater affinity to JAK1 versus JAK2, JAK3 and Tyk2. 63…”

“…Filgotinib is another selective JAK1 inhibitor, as it has more than fivefold greater affinity to JAK1 versus JAK2, JAK3 and Tyk2 63 . Winthrop et al recently reported a pooled safety analysis of seven RCTs of filgotinib in rheumatoid arthritis development program, in which 3691 patients received filgotinib for 6080.7 patient‐years of exposure (median 1.6, maximum 5.6 years) 64 .…”

Impfungen bei gastroenterologischen Erkrankungen und Immunsuppression

“…Für die JAK-Inhibitoren sind kürzere Halbwertszeiten beschrieben: Upadacitinib ca. 16 h 15 , Filgotinib 27,3 h 16 und Tofacitinib 3 h 17 . Hier ist wie bei Steroiden, Ciclosporin, Methotrexat und Tacrolimus eine Wartezeit von ca.…”