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.