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

Varun Kushwah,Dattatray Modhave,Miklós Tamás Katona,Amrit Paudel,Eleonore Fröhlich,Sumit Arora

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 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.

Highlights

Developing and deploying approaches that enable predicting the in vivo efficacy and safety profile of pharmaceutical drug products enormously expedite the product and process development effort as well as reduce the need for expensive clinical studies
The solubility of the Riva was found to be comparable among different media, i.e., water, fasted state simulated gastric fluid (FaSSGF), and fasted state simulated intestinal fluid (FaSSIF)
A conventional in vivo correlation (IVIVC) model was developed in order to verify the in vivo profile obtained via the physiologically based pharmacokinetic (PBPK) model

Summary

Introduction

Developing and deploying approaches that enable predicting the in vivo efficacy and safety profile of pharmaceutical drug products enormously expedite the product and process development effort as well as reduce the need for expensive clinical studies. A widely accepted approach to assess the correlation between in vitro dissolution and in vivo bioavailability of an immediate-release (IR) drug product is based on the Biopharmaceutics Classification System (BCS). In the case of IR drug products containing BCS Class II drug substance (dissolution as a rate-limiting step for absorption), conventional IVIVC can be used to establish the (cor)relation between the in vitro drug release and in vivo plasma concentration. For BCS Class III drugs (for which permeability is the rate-limiting step for absorption), limited or no IVIV correlation is expected with the dissolution rate. Drug products containing BCS Class IV drug substance (low solubility and low permeability) has to be evaluated case by case; these drugs exhibit poor and variable bioavailability [2,3]

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Conclusion