Application of Absorption Modeling to Predict Bioequivalence Outcome of Two Batches of Etoricoxib Tablets

Abstract

Abstract. As part of the overall product development and manufacturing strategy, pharmaceutical companies routinely change formulation and manufacturing site. Depending on the type and level of change and the BCS class of the molecule, dissolution data and/or bioequivalence (BE) may be needed to support the change for immediate release dosage forms. In this report, we demonstrate that for certain weakly basic low-solubility molecules which rapidly dissolve in the stomach, absorption modeling could be used to justify a BE study waiver even when there is failure to show dissolution similarity under some conditions. The development of an absorption model for etoricoxib is described here, which was then used to a priori predict the BE outcome of tablet batches manufactured at two sites. Dissolution studies in 0.01 N HCl media (pH 2.0) had demonstrated similarity of etoricoxib tablets manufactured at two different sites. However, dissolution testing at pH 4.5 and pH 6.8 media failed to show comparability of the tablets manufactured at the two sites. Single simulations and virtual trials conducted using the 0.01 N HCl dissolution showed similarity in AUC and C max for all tablet strengths for batches manufactured at the two manufacturing sites. These predicted results were verified in a definitive bioequivalence study, which showed that both tablet batches were bioequivalent. Since the development of traditional in vitro-in vivo correlations (IVIVC) for immediate release (IR) products is challenging, in cases such as etoricoxib, absorption modeling could be used as an alternative to support waiver of a BE study.

Physiologically Based Pharmacokinetic Modeling for Substitutability Analysis of Venlafaxine Hydrochloride Extended-Release Formulations Using Different Release Mechanisms: Osmotic Pump Versus Openable Matrix

“…Physiologically based pharmacokinetic (PBPK) modeling has been utilized to assess the food effect 33,34 , drug-drug interaction [35][36][37] , inter-batch quality variation 38 , in vivo performance in subpopulation 18 , and bioequivalence for generic drug evaluation 18,38,39 . In the current study, we extended such a PBPK approach to assess the in vivo PK and bioequivalence associated with formulation release mechanism change for oral ER venlafaxine HCl dosage forms based on an openable matrix design.…”

Developing Clinically Relevant Dissolution Specifications for Oral Drug Products—Industrial and Regulatory Perspectives

“…Mitra and colleagues generated dissolution profiles in multimedia to support a site transfer for etoricoxib, which is a BCS II drug [28]. The F2 similarity test failed at pH 4.5 and 6.8.…”

Approaches for Establishing Clinically Relevant Dissolution Specifications for Immediate Release Solid Oral Dosage Forms

“…For example, Zhang et al demonstrated how oral absorption/PBPK modeling could be used to understand the in vivo performance of generic IR and XR carbamezepine formulations and identify the important characteristics in the release mechanisms that should be reflected in a dissolution test (33). More recently, Mitra et al described the use of models to assess the impact of dissolution differences observed between batches manufactured at different sites for etoricoxib (34). The simulations showed that the dissolution differences (outside f 2 bounds) observed at pH 4.5 and 6.8 during multimedia testing were not clinically relevant, while the dissolution at pH 1.2 (f 2 > 50) would be a better predictor of clinical performance.…”