The biorelevant simulation of gastric emptying and its impact on model drug dissolution and absorption kinetics.

The highly variable physiological conditions within the gastrointestinal tract can cause variable drug release and absorption from the orally administrated dosage forms. The emptying of the gastric content is one of the most critical physiological processes, dictating the amount of the active ingredient available for absorption into the systemic circulation. In this study, we prepared two water gastric emptying regimes on advanced gastric simulator (AGS) with programmable "pyloric" valve. Gastric emptying regimes were designed in such a way to capture the main findings of the MRI (magnetic resonance imaging) in vivo studies, conducted under fasted conditions according to the EMA and FDA guidelines for bioavailability and bioequivalence studies. Four immediate release formulations containing a model drug of BCS class III were tested. Comparative dissolution tests were also performed with the USP2 apparatus. In vitro release profiles were compared to the in vivo data in order to evaluate the importance of gastric emptying for subsequent absorption of the active substance from the tested formulations. Our bio-relevant in vitro dissolution model showed good discriminatory power for all of the tested formulations. Moreover, a better relation to in vivo data was achieved with AGS with respect to the tested conventional dissolution method.

Biowaiver Monographs for Immediate Release Solid Oral Dosage Forms: Levetiracetam.

Literature and experimental data relevant for the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release (IR) solid oral dosage forms containing levetiracetam are reviewed. Data on solubility and permeability suggest that levetiracetam belongs to class I of the biopharmaceutical classification system (BCS). Levetiracetam's therapeutic use, its wide therapeutic index, and its favorable pharmacokinetic properties make levetiracetam a valid candidate for the BCS-based biowaiver approach. Further, no BE studies with levetiracetam IR formulations in which the test formulation failed to show BE with the comparator have been reported in the open literature. On the basis of the overall evidence, it appears unlikely that a BCS-based biowaiver approach for levetiracetam IR solid oral dosage forms formulated with established excipients would expose patients to undue risks. Thus, the BCS-based biowaiver approach procedure is recommended for IR solid oral dosage form containing levetiracetam, provided the excipients in the formulation are also present in products that have been approved in countries belonging to or associated with the International Committee on Harmonization and are used in their usual quantities, and provided the dissolution profiles of the test and reference product comply with the current requirements for BCS-based biowaivers.