An In Vivo Predictive Dissolution Methodology (iPD Methodology) with a BCS Class IIb Drug Can Predict the In Vivo Bioequivalence Results: Etoricoxib Products

Abstract

The purpose of this study was to predict in vivo performance of three oral products of Etoricoxib (Arcoxia® as reference and two generic formulations in development) by conducting in vivo predictive dissolution with GIS (Gastro Intestinal Simulator) and computational analysis. Those predictions were compared with the results from previous bioequivalence (BE) human studies. Product dissolution studies were performed using a computer-controlled multicompartmental dissolution device (GIS) equipped with three dissolution chambers, representing stomach, duodenum, and jejunum, with integrated transit times and secretion rates. The measured dissolved amounts were modelled in each compartment with a set of differential equations representing transit, dissolution, and precipitation processes. The observed drug concentration by in vitro dissolution studies were directly convoluted with permeability and disposition parameters from literature to generate the predicted plasma concentrations. The GIS was able to detect the dissolution differences among reference and generic formulations in the gastric chamber where the drug solubility is high (pH 2) while the USP 2 standard dissolution test at pH 2 did not show any difference. Therefore, the current study confirms the importance of multicompartmental dissolution testing for weak bases as observed for other case examples but also the impact of excipients on duodenal and jejunal in vivo behavior.

In Vivo Predictive Dissolution and Biopharmaceutic-Based In Silico Model to Explain Bioequivalence Results of Valsartan, a Biopharmaceutics Classification System Class IV Drug

“…The dissolution media, initial volumes, and secretion rates are described in Table 2. The transfer rate from the stomach to the duodenum was set as a first-order kinetic process with a gastric half-life of 8 min, in accordance with human data [11,12]. The volume of the stomach was decreasing from 300 mL to 10 mL.…”

“…The final permeability values are displayed in Table 7. Fsys 0.39 0.39 0.39 [11] k t (min −1 ) 0.0056 0.0056 0.0056 [15] tcut (min) 600 360 600 [11] k pre_s (min The gastric emptying times were shortened (from 15 to 13 min) for the VALS_Supra/ HCTZ BE formulation. These gastric emptying times were based on previous human intubation studies (13 min) with a 2 min delay in the formulation containing more sorbitol, based on the AUC and C max ratio differences for the HCTZ in both test products.…”

Analysis of Factors Related to Variation in Dissolution Profiles Estimated from Continuously Conducted Dissolution Tests of Generic Products

“…[23][24][25] In addition, it is necessary to control the dissolution of poorly soluble APIs because the dissolution process in the gastrointestinal tract is critical for BE. [26][27][28] We initially expected that products with poorly soluble APIs would be more dissimilar from those with highly soluble APIs. However, our study indicated that API solubility was not associated with changes in the dissolution profiles of the marketed products (Fig.…”

Quantification of Etoricoxib in Low Plasma Volume by UPLC-PDA and Application to Preclinical Pharmacokinetic Study

“…Etoricoxib is a lipophilic (logP = 2.8), and weakly basic drug (pKa = 5.0), showing low and pH-dependent aqueous solubility. It is classified as a BCS (biopharmaceutics classification system) class II compound [ 4 ].…”