Kourentas, Alexandros, Gajewska, Monika, Dhareshwar, Sundeep, Steib-Lauer, Caroline, Kulkarni, Swarupa, Hirsch, Stefan, Mueller-Zsigmondy, Martin, Wen, Lin and Tycho, Heimbach (2023) Establishing the clinical bioequivalence safe space via physiologically-based population pharmacokinetics absorption modeling. Case study: Fevipiprant/QAW039. Establishing the clinical bioequivalence safe space via physiologically-based population pharmacokinetics absorption modeling. Case study: Fevipiprant/QAW039, 25 ((1)). ISSN DOI: 10.1208/s12248-023-00787-5

Abstract

Physiologically based pharmacokinetics (PBPK) and absorption modeling has increasingly been implemented for biopharmaceutics applications to define the bioequivalence safe space for drug product quality attributes such as dissolution. For fevipiprant/QAW039, PBPK analyses were performed to assess the impact of in vitro dissolution on the in vivo PK performance of immediate release (IR) 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 tablet dissolution profiles were used as GastroPlusTM model inputs to estimate the in vivo dissolution in the GI tract, and to predict human exposure. The model was used to evaluate the intraluminal performance of the dosage forms and to determine 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 dissolution safe space boundaries at 450 mg, simulations were performed using theoretical dissolution profiles. A specification of Q=80% dissolved after 60 min for an IR oral solid dosage form reflected the limitations 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 failure for dissolution, providing additional confidence to the proposed acceptance criteria. Thus, the PBPK dissolution safe space allowed for a wider than 10% dissolution difference for bioequivalent batches, superseding f2 similarity analyses.

Item Type:	Article
Keywords:	GastroPlusTM, PBPK absorption modeling, virtual bioequivalence, clinically relevant dissolution specifications, twin-screw melt granulation
Date Deposited:	11 Mar 2023 00:45
Last Modified:	11 Mar 2023 00:45
URI:	https://oak.novartis.com/id/eprint/47049