Population PK Analysis
The final PopPK model development dataset for filgotinib included 13376 PK datapoints from 3125 subjects (details by study are provided in supplementary Table 1). Plasma concentrations of filgotinib were best described by a 2-compartment model with a mixture model for absorption and linear elimination. The two subpopulations for absorption, rapid versus slower, were described respectively by a first-order [with absorption rate constant (ka) being fixed to a high value to mimic an almost instantaneous absorption profile] and a sequential zero- first-order absorption. The model included a difference in bioavailability (F) between tablets and capsules. Weight effects were included on apparent central clearance (CL/F), apparent intercompartmental clearance (Q/F), central volume of distribution (Vc/F), and peripheral volume of distribution (Vp/F) using standard fixed allometric exponents of 0.75 for the clearance and 1 for the volume of distribution parameters. Moreover, baseline CRP and sex were identified as statistically significant covariates on filgotinib CL/F, whereas race (white and Asian versus black or African American versus other) was identified as a statistically significant covariate on Vc/F (supplementary Table 2). Although the final filgotinib model had a tendency to modestly underpredict Cmax (GMRs of 0.76-0.79 based on different populations), the model was able to adequately predict AUCtau with geometric mean ratio (GMR) = 0.98, and thus could be used to predict individual exposures for ER analyses.
For GS-829845, the final model development dataset included 14896 PK datapoints from 3155 subjects (details by study are provided in supplementary Table 1). Plasma concentrations of GS-829845 were best described by a 1-compartment model with first-order absorption, and first-order elimination. Statistically significant covariates included the effects of baseline CLcr, baseline CRP, patient status, and sex on CL/F; Asian race versus non-Asian race and duration of RA on V/F; and formulation on F and ka(supplementary Table 3).
The final models adequately described the plasma concentrations of filgotinib and GS-829845 separately, as assessed by diagnostic plots/metrics including Goodness-of-Fit evaluation, pcVPC, and Bootstrap Resampling (supplementary Tables 2-3 and supplementary Figures 2-5). Thus, the predicted individual PK exposures were deemed adequate to be used in the ER analyses.