Working Paper Article Version 1 This version is not peer-reviewed

On Absorption Modeling and Food Effect Prediction of Rivaroxaban, a BCS II Drug Orally Administered as an Immediate-Release Tablet

Version 1 : Received: 23 January 2021 / Approved: 25 January 2021 / Online: 25 January 2021 (09:41:41 CET)

A peer-reviewed article of this Preprint also exists.

Kushwah, V.; Arora, S.; Tamás Katona, M.; Modhave, D.; Fröhlich, E.; Paudel, A. On Absorption Modeling and Food Effect Prediction of Rivaroxaban, a BCS II Drug Orally Administered as an Immediate-Release Tablet. Pharmaceutics 2021, 13, 283. Kushwah, V.; Arora, S.; Tamás Katona, M.; Modhave, D.; Fröhlich, E.; Paudel, A. On Absorption Modeling and Food Effect Prediction of Rivaroxaban, a BCS II Drug Orally Administered as an Immediate-Release Tablet. Pharmaceutics 2021, 13, 283.

Journal reference: Pharmaceutics 2021, 13, 283
DOI: 10.3390/pharmaceutics13020283

Abstract

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® IR tablet in the fed state. Overall, the results obtained from the IVIVC model were found to be comparable with that from the PBPK model. The outcome from both the model 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.

Subject Areas

In vitro–In vivo Correlation; Physiologically Based Pharmacokinetic Model; BCS Class II; Rivaroxaban; Xarelto; Food Effect; Population Kinetics

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