Development of Physiologically Based Pharmacokinetic Model for Orally Administered Fexuprazan in Humans

Fexuprazan is a new drug candidate in the potassium-competitive acid blocker (P-CAB) family. As proton pump inhibitors (PPIs), P-CABs inhibit gastric acid secretion and can be used to treat gastric acid-related disorders such as gastroesophageal reflux disease (GERD). Physiologically based pharmacok...

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Bibliographic Details
Published in:Pharmaceutics 2021-05, Vol.13 (6), p.813
Main Authors: Jeong, Yoo-Seong, Kim, Min-Soo, Lee, Nora, Lee, Areum, Chae, Yoon-Jee, Chung, Suk-Jae, Lee, Kyeong-Ryoon
Format: Article
Language:English
Subjects:
Acids
Bioavailability
Blood
Clinical trials
Drug dosages
DWP14012
Enzymes
Esophagus
fexuprazan
Gastroesophageal reflux
human scaling
Kinetics
Liver
Metabolism
Metabolites
Older people
Permeability
Pharmacokinetics
physiologically based pharmacokinetic modeling
Physiology
Plasma
potassium-competitive acid blocker
Proteins
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Summary:Fexuprazan is a new drug candidate in the potassium-competitive acid blocker (P-CAB) family. As proton pump inhibitors (PPIs), P-CABs inhibit gastric acid secretion and can be used to treat gastric acid-related disorders such as gastroesophageal reflux disease (GERD). Physiologically based pharmacokinetic (PBPK) models predict drug interactions as pharmacokinetic profiles in biological matrices can be mechanistically simulated. Here, we propose an optimized and validated PBPK model for fexuprazan by integrating in vitro, in vivo, and in silico data. The extent of fexuprazan tissue distribution in humans was predicted using tissue-to-plasma partition coefficients in rats and the allometric relationships of fexuprazan distribution volumes (VSS) among preclinical species. Urinary fexuprazan excretion was minimal (0.29–2.02%), and this drug was eliminated primarily by the liver and metabolite formation. The fraction absorbed (Fa) of 0.761, estimated from the PBPK modeling, was consistent with the physicochemical properties of fexuprazan, including its in vitro solubility and permeability. The predicted oral bioavailability of fexuprazan (38.4–38.6%) was within the range of the preclinical datasets. The Cmax, AUClast, and time-concentration profiles predicted by the PBPK model established by the learning set were accurately predicted for the validation sets.
ISSN:1999-4923
1999-4923
DOI:10.3390/pharmaceutics13060813