The PBPK model of substrates
In our previous work, we reported the primary modeling parameters and
fundamental PK models for 33 compounds. In this study, we utilized thein vitro measured fm value to characterize
the contribution of the CYP3A4 enzyme to liver clearance. As a result,
we updated the clearance in the PBPK model from
Clsys = ClCYP3A4 + ClR
to
Clsys = ClCYP3A4 +
Clother + ClR
where Clsys is the total in vivo clearance,
ClCYP3A4 is the clearance mediated by CYP3A4,
Clother is the clearance mediated by other metabolism
enzymes, and ClR is the clearance mediated by the
kidney. The PBPK models of the substrates after administration alone
were validated by visual comparison of the coincidence between the
predicted PK curve and the clinical observations as showed in Figure S2.
To define in vitro fm in the PBPK models, we
assumed that it conforms to linear dynamics in the Mieman equation,
which means assigning a value much larger than S to Km.
As a result, the initial Vmax can be calculated simply
using the following formula, and the final Vmax was
fitted by comparing the fm of CYP3A4 in the
updated PBPK models with corresponding in vitro
fm as well as evaluating the performance of PK
predictions.
Vmax = ClCYP3A4 ยท Km