Pharmacokinetics and Pharmacokinetic/Pharmacodynamic Modeling of Filgotinib (GLPG0634), a Selective JAK1 Inhibitor, in Support of Phase IIB Dose Selection

Abstract

Background and objectives: Filgotinib (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.

Methods: Two 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.

Results: Modeling 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.

Conclusion: Based 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.

Trial registration: ClinicalTrials.gov NCT01179581 NCT01384422 NCT01419990.

Figures

Fig. 1

Structure of filgotinib and its active metabolite

Fig. 2

Mean (±standard error) plasma concentrations of filgotinib and its metabolite after single (a, b) and repeated (c, d) administration of filgotinib given as capsules in fed healthy male volunteers (n = 6 per dose group). b.i.d. bis in die (twice daily), q.d. quaque in die (once daily)

Fig. 3

Schematic for the combined structural model describing the pharmacokinetics of filgotinib and its active metabolite. CLP, CLM total filgotinib and metabolite clearance, respectively, FRAC fraction of filgotinib metabolized through secondary pathway of elimination, ka first-order absorption rate constant, Q filgotinib intercompartmental clearance, VC/F, VP/F, VM/F apparent filgotinib central, filgotinib peripheral, and metabolite volume of distribution, respectively

Fig. 4

Goodness-of-fit assessment comparing observed filgotinib and metabolite concentrations with the corresponding population predictions (a) and Q–Q plot of conditional weighted residuals (b). Solid line shows line of unity. Residual-based diagnostics for pharmacokinetic model (c–f) with horizontal solid and dotted lines at zero and ±1.96, respectively. CWRES conditional weighted residuals

Fig. 5

Mean observed filgotinib (a) and metabolite (b) plasma concentration–time profiles after once-daily dosing at 200 mg. Small markers show the individual observed filgotinib and metabolite plasma concentrations on day 1 and 10 at 0.5, 1, 2, 3, 5, 8, and 12 h post-dose, with the mean (95 % confidence interval) shown with large markers (error bars). Thick solid lines show the corresponding mean population predictions based on the final population pharmacokinetic model

Fig. 6

Goodness-of-fit assessment comparing observed pSTAT1 response to the corresponding population predictions (a) and Q–Q plot of conditional weighted residuals (b). Solid line shows line of unity. Residual-based diagnostics for the final model of pSTAT1 response (c–f) with horizontal solid and dotted lines show at zero and ±1.96, respectively. CWRES conditional weighted residuals

Fig. 7

Estimated exposure-response relation between filgotinib (a) and metabolite (b) plasma concentrations and the proportion of pSTAT1-positive cells (95 % confidence interval). Vertical line segments indicate the filgotinib and metabolite concentrations leading to 50 % inhibition of the pSTAT1 signal compared with placebo

Fig. 8

Simulated steady-state inhibition of pSTAT1 with 90 % confidence interval. Black and gray curves show model-predicted filgotinib and metabolite plasma concentrations, respectively (common arbitrary units). b.i.d. bis in die (twice daily), q.d. quaque in die (once daily)