1. Physiologically Based Biopharmaceutics Modeling for Gefapixant IR Formulation Development and Defining the Bioequivalence Dissolution Safe Space.
- Author
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Wang M, Heimbach T, Zhu W, Wu D, Reuter KG, and Kesisoglou F
- Subjects
- Humans, Proton Pump Inhibitors pharmacokinetics, Proton Pump Inhibitors administration & dosage, Proton Pump Inhibitors chemistry, Biological Availability, Biopharmaceutics methods, Drug Liberation, Omeprazole pharmacokinetics, Omeprazole administration & dosage, Omeprazole chemistry, Administration, Oral, Hydrogen-Ion Concentration, Tablets, Drug Interactions, Chemistry, Pharmaceutical methods, Cross-Over Studies, Drug Compounding methods, Therapeutic Equivalency, Models, Biological, Solubility
- Abstract
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.)
- Published
- 2024
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