2.2.1 Population PK/PD model and simulation
A previously published population PK/PD model of edoxaban was used in
our study 23. . To the best of our knowledge, this is
the only published combined PK and PD model. This model was developed
based on phase I and phase II studies. A total of 1,624 healthy subjects
and NVAF patients were enrolled in the PK analysis, and a total of 585
NVAF patients were enrolled in the PD analysis. PK was described by a
two-compartment model with first-order absorption with lag time and
first-order elimination. The intrinsic FXa activity (iFXa) was selected
as a PD marker and was modelled using a dynamic binding and equilibrium
model. The PD data were modeled using dynamic binding model and
equilibrium model. A summary of the demographic information of the
modelling population is presented in Supplementary Table 1. The PK/PD
model and all parameter estimates employed in the Monte Carlo simulation
are listed in Table 2.
Monte Carlo simulations were performed with RXODE (version 0.9.1-8) in R
(version 3.6.1) 24. Under each non-adherence scenario,
one thousand virtual patients were simulated to obtain both the PK and
PD profiles. The patients were assumed to reach a steady state before
the delayed dose. Additionally, it was assumed that the current dose was
sufficient to produce the desired anticoagulation effect without
undesirable adverse effects.