The present work evaluates the food effect on the absorption of rivaroxaban (Riva),
a BCS II drug, from the orally administered commercial immediate-release tablet (Xarelto
IR) using physiologically based pharmacokinetic (PBPK) and conventional in vitro-in
vivo correlation (IVIVC) models. The bioavailability of Riva upon oral administration
of Xarelto IR tablet is reported to exhibit a positive food effect. The PBPK model
for Riva was developed and verified using the previously reported in vivo data for
oral solution (5 and 10 mg) and Xarelto IR tablet (5 and 10 mg dose strength). Once
the PBPK model was established, the in vivo performance of the tablet formulation
with the higher dose strength (Xarelto IR tablet 20 mg in fasted and fed state) was
predicted using the experimentally obtained data of in vitro permeability, biorelevant
solubility and in vitro dynamic dissolution data using United States Pharmacopeia
(USP) IV flow-through cell apparatus. In addition, the mathematical IVIVC model was
developed using the in vitro dissolution and in vivo profile of 20 mg strength Xarelto
IR tablet in fasted condition. Using the developed IVIVC model, the pharmacokinetic
(PK) profile of the Xarelto IR tablet in fed condition was predicted and compared
with the PK parameters obtained via the PBPK model. A virtual in vivo PK study was
designed using a single-dose, 3-treatment cross-over trial in 50 subjects to predict
the PK profile of the Xarelto (R) IR tablet in the fed state. Overall, the results
obtained from the IVIVC model were found to be comparable with those from the PBPK
model. The outcome from both models pointed to the positive food effect on the in
vivo profile of the Riva. The developed models thus can be effectively extended to
establish bioequivalence for the marketed and novel complex formulations of Riva such
as amorphous solid dispersions.
