• Florence Namour, Paul Matthias Diderichsen, Eugène Cox, Béatrice Vayssière, Annegret Van der Aa, Chantal Tasset, and Gerben Van't Klooster.
• Galapagos SASU, 102 Avenue Gaston Roussel, 93230, Romainville, France, florence.namour@glpg.com.
• Clin Pharmacokinet. 2015 Aug 1; 54 (8): 859-74.

Background And ObjectivesFilgotinib (GLPG0634) is a selective inhibitor of Janus kinase 1 (JAK1) currently in development for the treatment of rheumatoid arthritis and Crohn's disease. While less selective JAK inhibitors have shown long-term efficacy in treating inflammatory conditions, this was accompanied by dose-limiting side effects. Here, we describe the pharmacokinetics of filgotinib and its active metabolite in healthy volunteers and the use of pharmacokinetic-pharmacodynamic modeling and simulation to support dose selection for phase IIB in patients with rheumatoid arthritis.MethodsTwo trials were conducted in healthy male volunteers. In the first trial, filgotinib was administered as single doses from 10 mg up to multiple daily doses of 200 mg. In the second trial, daily doses of 300 and 450 mg for 10 days were evaluated. Non-compartmental analysis was used to determine individual pharmacokinetic parameters for filgotinib and its metabolite. The overall pharmacodynamic activity for the two moieties was assessed in whole blood using interleukin-6-induced phosphorylation of signal-transducer and activator of transcription 1 as a biomarker for JAK1 activity. These data were used to conduct non-linear mixed-effects modeling to investigate a pharmacokinetic/pharmacodynamic relationship.ResultsModeling and simulation on the basis of early clinical data suggest that the pharmacokinetics of filgotinib are dose proportional up to 200 mg, in agreement with observed data, and support that both filgotinib and its metabolite contribute to its pharmacodynamic effects. Simulation of biomarker response supports that the maximum pharmacodynamic effect is reached at a daily dose of 200 mg filgotinib.ConclusionBased on these results, a daily dose range up to 200 mg has been selected for phase IIB dose-finding studies in patients with rheumatoid arthritis.

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