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...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2021-05-01
|
| Series: | Pharmaceutics |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1999-4923/13/6/813 |
| _version_ | 1797532036048617472 |
|---|---|
| author | Yoo-Seong Jeong Min-Soo Kim Nora Lee Areum Lee Yoon-Jee Chae Suk-Jae Chung Kyeong-Ryoon Lee |
| author_facet | Yoo-Seong Jeong Min-Soo Kim Nora Lee Areum Lee Yoon-Jee Chae Suk-Jae Chung Kyeong-Ryoon Lee |
| author_sort | Yoo-Seong Jeong |
| collection | DOAJ |
| description | 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 (<i>V<sub>SS</sub></i>) 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 (<i>Fa</i>) 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 C<sub>max</sub>, AUC<sub>last</sub>, and time-concentration profiles predicted by the PBPK model established by the learning set were accurately predicted for the validation sets. |
| first_indexed | 2024-03-10T10:53:20Z |
| format | Article |
| id | doaj.art-180d46ad5a7c4abdb2561d4c91acb987 |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-10T10:53:20Z |
| publishDate | 2021-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj.art-180d46ad5a7c4abdb2561d4c91acb9872023-11-21T22:02:16ZengMDPI AGPharmaceutics1999-49232021-05-0113681310.3390/pharmaceutics13060813Development of Physiologically Based Pharmacokinetic Model for Orally Administered Fexuprazan in HumansYoo-Seong Jeong0Min-Soo Kim1Nora Lee2Areum Lee3Yoon-Jee Chae4Suk-Jae Chung5Kyeong-Ryoon Lee6College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, KoreaCollege of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, KoreaDaewoong Pharmaceutical Co., Ltd., Seoul 06170, KoreaDaewoong Pharmaceutical Co., Ltd., Seoul 06170, KoreaCollege of Pharmacy, Woosuk University, Wanju-gun 55338, KoreaCollege of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, KoreaLaboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju 28116, KoreaFexuprazan 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 (<i>V<sub>SS</sub></i>) 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 (<i>Fa</i>) 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 C<sub>max</sub>, AUC<sub>last</sub>, and time-concentration profiles predicted by the PBPK model established by the learning set were accurately predicted for the validation sets.https://www.mdpi.com/1999-4923/13/6/813DWP14012fexuprazanhuman scalingphysiologically based pharmacokinetic modelingpotassium-competitive acid blocker |
| spellingShingle | Yoo-Seong Jeong Min-Soo Kim Nora Lee Areum Lee Yoon-Jee Chae Suk-Jae Chung Kyeong-Ryoon Lee Development of Physiologically Based Pharmacokinetic Model for Orally Administered Fexuprazan in Humans Pharmaceutics DWP14012 fexuprazan human scaling physiologically based pharmacokinetic modeling potassium-competitive acid blocker |
| title | Development of Physiologically Based Pharmacokinetic Model for Orally Administered Fexuprazan in Humans |
| title_full | Development of Physiologically Based Pharmacokinetic Model for Orally Administered Fexuprazan in Humans |
| title_fullStr | Development of Physiologically Based Pharmacokinetic Model for Orally Administered Fexuprazan in Humans |
| title_full_unstemmed | Development of Physiologically Based Pharmacokinetic Model for Orally Administered Fexuprazan in Humans |
| title_short | Development of Physiologically Based Pharmacokinetic Model for Orally Administered Fexuprazan in Humans |
| title_sort | development of physiologically based pharmacokinetic model for orally administered fexuprazan in humans |
| topic | DWP14012 fexuprazan human scaling physiologically based pharmacokinetic modeling potassium-competitive acid blocker |
| url | https://www.mdpi.com/1999-4923/13/6/813 |
| work_keys_str_mv | AT yooseongjeong developmentofphysiologicallybasedpharmacokineticmodelfororallyadministeredfexuprazaninhumans AT minsookim developmentofphysiologicallybasedpharmacokineticmodelfororallyadministeredfexuprazaninhumans AT noralee developmentofphysiologicallybasedpharmacokineticmodelfororallyadministeredfexuprazaninhumans AT areumlee developmentofphysiologicallybasedpharmacokineticmodelfororallyadministeredfexuprazaninhumans AT yoonjeechae developmentofphysiologicallybasedpharmacokineticmodelfororallyadministeredfexuprazaninhumans AT sukjaechung developmentofphysiologicallybasedpharmacokineticmodelfororallyadministeredfexuprazaninhumans AT kyeongryoonlee developmentofphysiologicallybasedpharmacokineticmodelfororallyadministeredfexuprazaninhumans |