Physiologically based pharmacokinetic combined JAK2 occupancy modelling
to simulate PK and PD of baricitinib with kidney transporter inhibitors
and in patients with hepatic/renal impairment
Our aim is to build a physiologically based pharmacokinetic and JAK2
occupancy model (PBPK-JO) to simultaneously predict pharmacokinetic (PK)
and pharmacodynamic (PD) changes of baricitinib (BAR) in healthy human
when co-administration with kidney transporters OAT3 and MATE2-K
inhibitors, and in patients with hepatic and renal impairment.
Probenecid and vandetanib were selected as OAT3 and MATE2-K competitive
inhibitors, respectively. Here, we have successfully simulated PK and
JAK2 occupancy profiles in human by PBPK-JO model. Moreover, this
modelling reproduced every observed PK data, and every mean relative
deviation (MRD) were below 2. The simulation demonstrated that oral dose
of BRA should be reduced to half when co-administration with probenecid.
The prediction suggested also vandetanib was unlikely to affect PK and
PD of BAR. In simulations of hepatic and renal impairment patients, the
predictions suggested that significant changes in PK and PD of BAR
occurred. However, there was a lower fold increase in JAK2 occupancies
than in PK in patients relative to healthy individuals. In other words,
administration dose adjustment of BAR in patients with hepatic or renal
impairment should combine PK and PD changes of BAR, instead off only
considering PK alteration.