Establishing the Safe Space via Physiologically Based Biopharmaceutics Modeling. Case Study: Fevipiprant/QAW039

AbstractPhysiologically based pharmacokinetic and absorption modeling has increasingly been implemented for biopharmaceutics applications to define the safe space for drug product quality attributes such as dissolution. For fevipiprant/QAW039, simulations were performed to assess the impact ofin vitro dissolution on thein vivo performance of immediate-release film-coated tablets during development and scaling up to commercial scale. A fevipiprant dissolution safe space was established using observed clinical intravenous and oral PK data from bioequivalent and non-bioequivalent formulations. Quality control dissolution profiles with tablets were used as GastroPlus ™ model inputs to estimate thein vivo dissolution in the gastrointestinal tract and to simulate human exposure. The model was used to evaluate the intraluminal performance of the dosage forms and to predict the absorption rate limits for the 450  mg dose. The predictive model performance was demonstrated for various oral dosage forms (150‒500 mg), including the non-bioequivalent batches in fasted healthy adults. To define the safe space at 450 mg, simulations were performed using theoretical dissolution profiles. A specification of Q  = 80% dissolved in 60 min or less for an immediate-release oral solid dosage form reflected the boundaries of the safe space. The dissolution profile of the 450 mg commercial scale batch was within a dissolution region where bioequivalence is anticipated, not near an edge of...
Source: The AAPS Journal - Category: Drugs & Pharmacology Source Type: research