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).  Its once-daily oral administration is supported by the long half-life of an active metabolite with the same JAK1 selectivity profile as the parent compound. Given genetics may cause differences in drug metabolism and pharmacokinetics (PK), and pharmacodynamics (PD) resulting in variability in clinical response, filgotinib was studied in Japanese healthy volunteers to evaluate the potential for different dosing requirements compared to Caucasians/ Compare the PK, PD and safety of filgotinib between Japanese and Caucasian healthy volunteers after repeated dosing of 200 mg filgotinib.

Methods: In a single-center Phase 1 study, 10 Japanese (1^st and 2^nd generation residing outside Japan for less than 5 years) and 10 Caucasian healthy volunteers received once daily 200 mg filgotinib or placebo for 10 days. The PK of filgotinib and its main active metabolite were evaluated, and the overall PD effect was assessed in whole blood using ex vivo IL-6 induced phosphorylation of STAT1 (pSTAT1) as biomarker for JAK1 activity and GM-CSF induced phosphorylation of STAT5 (pSTAT5) for JAK2 activity. Standard safety assessments were performed throughout the study duration.

Results: Steady state in plasma concentrations for filgotinib and its active metabolite was attained after 2 to 3 days of administration in both Japanese and Caucasian volunteers. Overall exposures for filgotinib and its metabolite were similar in the two groups, with the main active metabolite showing plasma concentrations well exceeding those of filgotinib. Both in Japanese and Caucasians, IL-6 induced pSTAT1 was inhibited over the entire 24 hour post-dosing period, with maximum inhibition observed between 1 and 5 hours post dose. No relevant inhibition of JAK2 activity was observed in any group, confirming filgotinib’s selective inhibition of JAK1 over JAK2. In Japanese and Caucasian healthy volunteers, filgotinib was generally safe and well tolerated with no relevant differences in safety profile among the ethnic groups.

Conclusion: Filgotinib showed comparable PK, PD and safety profiles in Japanese and Caucasian healthy volunteers. The similarity in the PK and PD response suggests that there are no relevant differences among the groups in drug metabolism or selective inhibition of JAK1. These data support that filgotinib may be administered at similar doses in Japanese and Caucasian RA patients.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/filgotinib-glpg0634-a-selective-jak1-inhibitor-shows-similar-pharmacokinetics-and-pharmacodynamics-profiles-in-japanese-and-caucasian-healthy-volunteers/