Influence of age and renal impairment on the steady state pharmacokinetics of filgotinib, a selective JAK1 inhibitor

Abstract

AimsFilgotinib (GS‐6034, formerly GLPG0634) is an oral, selective Janus kinase 1 (JAK1) inhibitor that showed early response and sustained efficacy in patients with rheumatoid arthritis and with Crohn's disease. The aim of the present study was to investigate the impact of age and renal impairment (RI) on the pharmacokinetics (PK) of filgotinib and its main metabolite.MethodsThe effect of age was assessed in two groups of 10 elderly healthy subjects (65–74 and ≥75 years of age) and a control group of 10 younger healthy subjects (40–50 years of age). The impact of RI was investigated in three groups of subjects with mild (n = 6), moderate (n = 6) and severe (n = 3) RI [estimated glomerular filtration rate (eGFR) 60–89, 30–59 and 15–29 ml min–1 1.73 m–2, respectively] and a control group (n = 9) with normal renal function (eGFR ≥90 ml min–1 1.73 m–2). The PK of filgotinib and its metabolite were evaluated following filgotinib 100 mg once‐daily doses for 10 days.ResultsAt steady state, the exposure [area under the concentration–time curve over the dosing interval (AUC0–24 h)] of filgotinib and its metabolite was moderately higher (1.45‐ and 1.33‐fold, respectively) in the elderly subjects (≥75 years) compared with younger subjects. Renal clearance for filgotinib and its metabolite decreased with the degree of RI, leading to a maximum increase in AUC0–24 h of 1.54‐fold for filgotinib and 2.74‐fold for the metabolite in subjects with severe RI. Filgotinib was generally safe and well tolerated.ConclusionsAge and mild to moderate impairment of renal function had limited impact on the PK of filgotinib. In subjects with severe RI, the exposure to the metabolite of filgotinib was elevated, consistent with its renal elimination pathway.

Innovative rheumatologische und osteologische Medikation im Kontext der chronischen Niereninsuffizienz – Was ist möglich?

“…In einer experimentellen Studie konnte gezeigt werden, dass eine leicht bis moderat eingeschränkte Nierenfunktion (Stadium CKD G2, G3a und G3b) keinen Einfluss auf die Plasmakonzentration von Filgotinib aufweist. Bei Patienten mit einer chronischen Niereninsuffizienz im Stadium CKD G4 (eGFR 29-15 ml/min/1,73m²) kommt es durch die primäre renale Elimination von Filgotinib und sein Hauptmetabolit zu einem Anstieg der Plasmakonzentration [27].…”

Filgotinib, a JAK1 Inhibitor, Has No Effect on QT Interval in Healthy Subjects

“…Hepatic impairment does not significantly impact the pharmacokinetics (PK) of filgotinib as it is primarily metabolized by carboxylesterase isoform 2, enzyme systems that are present in high levels throughout the body. 7,16 Moderate hepatic impairment had no clinically relevant impact on the C max of filgotinib or metabolite. 17 Mild to moderate renal impairment has not been shown to impact the C max of filgotinib.…”

“…6 Filgotinib is primarily metabolized by carboxylesterase isoform 2, resulting in the loss of the cyclopropyl carboxylic acid group and formation of its major, circulating metabolite, which is predominantly excreted in the urine (>80%). 7,8 The metabolite also exhibits selective JAK1 inhibition, with approximately 16-to 20-fold higher exposure and longer half-life (23-27 hours for the metabolite versus 5-6 hours for filgotinib) but ß19-fold lower potency than filgotinib. 7,9,10 In phase 2 studies, filgotinib has shown clinical efficacy, rapid onset of activity, and a favorable safety and tolerability profile both as monotherapy and in combination with methotrexate in subjects with moderate to severe rheumatoid arthritis, [11][12][13] and in subjects with moderate to severe Crohn's disease.…”

“…7,8 The metabolite also exhibits selective JAK1 inhibition, with approximately 16-to 20-fold higher exposure and longer half-life (23-27 hours for the metabolite versus 5-6 hours for filgotinib) but ß19-fold lower potency than filgotinib. 7,9,10 In phase 2 studies, filgotinib has shown clinical efficacy, rapid onset of activity, and a favorable safety and tolerability profile both as monotherapy and in combination with methotrexate in subjects with moderate to severe rheumatoid arthritis, [11][12][13] and in subjects with moderate to severe Crohn's disease. 14 Safety pharmacology studies conducted in vitro and in dogs have indicated that filgotinib has a low risk of QTc interval prolongation.…”

“…The C max of metabolite was not altered by mild renal impairment, but was increased ß44% in subjects with moderate renal impairment. 7 Neither filgotinib nor its metabolite are substrates of cytochrome P450 or major drug transporters except for P-glycoprotein. Coadministration of filgotinib with itraconazole (a potent P-glycoprotein inhibitor) increased the C max of filgotinib by ß64% but did not change metabolite PK.…”