Single Dose Bioequivalence Study of Two Rivaroxaban Tablet Formulations, Administered Orally after Being Crushed and Suspended in Apple Puree

Abstract

The bioavailability of an active substance might be altered when a solid oral dosage form (SODF) is crushed or disintegrated and mixed with fluids or food in order to assist swallowing. In consequence, the current European Medicines Agency (EMA) practice is to request comparative bioavailability testing for bridging safety and efficacy data from a formulation administered whole to the same product administered crushed. Specific criteria for waiving in vivo testing of crushed products are available only for BCS Class I and Class III drugs. Since rivaroxaban is a Class II drug which can be administered crushed and mixed with fluids, any generic formulation has to be tested against the originator in this setting. Therefore, an open label, randomized, single dose, two-period, two-sequence, crossover bioequivalence study with administration of rivaroxaban 10 mg crushed tablets suspended in apple puree was conducted in 24 fasting healthy volunteers. Both rivaroxaban treatments were well tolerated by the study subjects. A standardized, dose efficient and fully reproducible protocol for grinding, mixing and administering investigational medicinal products was developed and applied. Assessment of bioequivalence was based on plasma concentrations of parent rivaroxaban, quantified using a validated HPLC/MS/MS method. The 90% confidence intervals for C max and AUC 0-t least square mean T/R ratios were within the bioequivalence acceptance range of 80% to 125%. Results from the present study reinforced the bioequivalence conclusion reached for the same test and reference products following administration of whole tablets in fasting state. No notable changes in bioavailability occurred when rivaroxaban tablets were crushed, immediately dispensed in 70 mL apple puree and quantitatively (entire dose recovered) administered to fasting volunteers.

A Single‐blind, Randomized, Single‐dose, Two‐sequence, Two‐period, Crossover Study to Assess the Bioequivalence between Two Oral Tablet Formulations of Rivaroxaban 20 mg in Healthy Mexican Volunteers

“…2 DOACs have been commonly used in Mexico since 2008. 10 Although the pharmacokinetic profile of rivaroxaban has been previously studied, 2,11,12 no data are available in a Mexican population. This phase I trial was conducted to demonstrate the bioequivalence of 2 oral tablet formulations of rivaroxaban 20 mg in a selected population of healthy Mexican volunteers under fed conditions.…”