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Gefapixant is a weakly basic drug which has been formulated as an immediate release tablet for oral administration. A physiologically based biopharmaceutics model (PBBM) was developed based on gefapixant physicochemical properties and clinical pharmacokinetics to aid formulation selection, bioequivalence safe space assessment and dissolution specification settings. In vitro dissolution profiles of different free base and citrate salt formulations were used as an input to the model. The model was validated against the results of independent studies, which included a bioequivalence and a relative bioavailability study, as well as a human ADME study, all meeting acceptance criteria of prediction errors ≤ 20% for both Cmax and AUC.  PBBM was also applied to evaluate gastric pH-mediated drug-drug-interaction potential with co-administration of a proton pump inhibitor (PPI), omeprazole. Model results showed good agreement with clinical data in which omeprazole lowered gefapixant exposure for the free base formulation but did not significantly alter gefapixant pharmacokinetics for the citrate based commercial drug product. An extended virtual dissolution bioequivalence safe space was established.  Gefapixant drug product batches are anticipated to be bioequivalent with the clinical reference batch when their dissolution is > 80% in 60 minutes. PBBM established a wide dissolution bioequivalence space as part of assuring product quality., (© 2024. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.)

The USP Rotating Basket Dissolution Testing Apparatus 1 is listed in the USP as one of the tools to assess dissolution of oral solid dosage forms. Baskets of different mesh sizes can be used to differentiate between dissolution profiles of different formulations. Here, we used Particle Image Velocimetry (PIV) to study the hydrodynamics of the USP Apparatus 1 using baskets with different mesh openings (10-, 20- and 40-mesh) revolving at 100 rpm, when the vessel was filled with 500 mL. The velocity profiles throughout the liquid were found to vary significantly using baskets of different mesh sizes, typically increasing with increased size of the opening of the basket mesh, especially for axial and radial velocities. This, in turn, resulted in a significantly different flow rate through the basket, which can be expected to significantly impact the dissolution rate of the drug product. A comparison between the results of this work with those of a previous study with a 900-mL fill volume (Sirasitthichoke et al., Intern. J. Pharmaceutics, 2021, 607: 120976), shows that although the hydrodynamics in the USP Apparatus 1 changed with fill level in the vessel, the flow rate through the basket was not significantly affected. This implies that tablets dissolving in the two systems would experience similar tablet-liquid medium mass transfer coefficients, and therefore similar initial dissolution rates, but different dissolution profiles because of the difference in volume., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)