Prediction of Drug–Drug Interaction Potential of Tegoprazan Using Physiologically Based Pharmacokinetic Modeling and Simulation
This study aimed to develop a physiologically based pharmacokinetic (PBPK) model of tegoprazan and to predict the drug–drug interaction (DDI) potential between tegoprazan and cytochrome P450 (CYP) 3A4 perpetrators. The PBPK model of tegoprazan was developed using SimCYP Simulator<sup>®</sup...
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| Format: | Article |
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MDPI AG
2021-09-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/13/9/1489 |
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| author | Deok Yong Yoon SeungHwan Lee In-Jin Jang Myeongjoong Kim Heechan Lee Seokuee Kim Bongtae Kim Geun Seog Song Su-jin Rhee |
| author_facet | Deok Yong Yoon SeungHwan Lee In-Jin Jang Myeongjoong Kim Heechan Lee Seokuee Kim Bongtae Kim Geun Seog Song Su-jin Rhee |
| author_sort | Deok Yong Yoon |
| collection | DOAJ |
| description | This study aimed to develop a physiologically based pharmacokinetic (PBPK) model of tegoprazan and to predict the drug–drug interaction (DDI) potential between tegoprazan and cytochrome P450 (CYP) 3A4 perpetrators. The PBPK model of tegoprazan was developed using SimCYP Simulator<sup>®</sup> and verified by comparing the model-predicted pharmacokinetics (PKs) of tegoprazan with the observed data from phase 1 clinical studies, including DDI studies. DDIs between tegoprazan and three CYP3A4 perpetrators were predicted by simulating the difference in tegoprazan exposure with and without perpetrators, after multiple dosing for a clinically used dose range. The final PBPK model adequately predicted the biphasic distribution profiles of tegoprazan and DDI between tegoprazan and clarithromycin. All ratios of the predicted-to-observed PK parameters were between 0.5 and 2.0. In DDI simulation, systemic exposure to tegoprazan was expected to increase about threefold when co-administered with the maximum recommended dose of clarithromycin or ketoconazole. Meanwhile, tegoprazan exposure was expected to decrease to ~30% when rifampicin was co-administered. Based on the simulation by the PBPK model, it is suggested that the DDI potential be considered when tegoprazan is used with CYP3A4 perpetrator, as the acid suppression effect of tegoprazan is known to be associated with systemic exposure. |
| first_indexed | 2024-03-10T07:18:26Z |
| format | Article |
| id | doaj.art-8aa6e5a4b6eb431b92e05edbac01cd09 |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-10T07:18:26Z |
| publishDate | 2021-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj.art-8aa6e5a4b6eb431b92e05edbac01cd092023-11-22T14:48:31ZengMDPI AGPharmaceutics1999-49232021-09-01139148910.3390/pharmaceutics13091489Prediction of Drug–Drug Interaction Potential of Tegoprazan Using Physiologically Based Pharmacokinetic Modeling and SimulationDeok Yong Yoon0SeungHwan Lee1In-Jin Jang2Myeongjoong Kim3Heechan Lee4Seokuee Kim5Bongtae Kim6Geun Seog Song7Su-jin Rhee8Department of Clinical Pharmacology and Therapeutics, College of Medicine and Hospital, Seoul National University, Seoul 03080, KoreaDepartment of Clinical Pharmacology and Therapeutics, College of Medicine and Hospital, Seoul National University, Seoul 03080, KoreaDepartment of Clinical Pharmacology and Therapeutics, College of Medicine and Hospital, Seoul National University, Seoul 03080, KoreaDivision of Clinical Development, HK inno.N Corporation, Seoul 04551, KoreaDivision of Clinical Development, HK inno.N Corporation, Seoul 04551, KoreaDivision of Clinical Development, HK inno.N Corporation, Seoul 04551, KoreaDivision of Clinical Development, HK inno.N Corporation, Seoul 04551, KoreaDivision of Clinical Development, HK inno.N Corporation, Seoul 04551, KoreaDepartment of Pharmacy, College of Pharmacy, Wonkwang University, Iksan 54538, KoreaThis study aimed to develop a physiologically based pharmacokinetic (PBPK) model of tegoprazan and to predict the drug–drug interaction (DDI) potential between tegoprazan and cytochrome P450 (CYP) 3A4 perpetrators. The PBPK model of tegoprazan was developed using SimCYP Simulator<sup>®</sup> and verified by comparing the model-predicted pharmacokinetics (PKs) of tegoprazan with the observed data from phase 1 clinical studies, including DDI studies. DDIs between tegoprazan and three CYP3A4 perpetrators were predicted by simulating the difference in tegoprazan exposure with and without perpetrators, after multiple dosing for a clinically used dose range. The final PBPK model adequately predicted the biphasic distribution profiles of tegoprazan and DDI between tegoprazan and clarithromycin. All ratios of the predicted-to-observed PK parameters were between 0.5 and 2.0. In DDI simulation, systemic exposure to tegoprazan was expected to increase about threefold when co-administered with the maximum recommended dose of clarithromycin or ketoconazole. Meanwhile, tegoprazan exposure was expected to decrease to ~30% when rifampicin was co-administered. Based on the simulation by the PBPK model, it is suggested that the DDI potential be considered when tegoprazan is used with CYP3A4 perpetrator, as the acid suppression effect of tegoprazan is known to be associated with systemic exposure.https://www.mdpi.com/1999-4923/13/9/1489tegoprazanphysiologically based pharmacokineticsdrug–drug interactionCYP3A4potassium-competitive acid blocker |
| spellingShingle | Deok Yong Yoon SeungHwan Lee In-Jin Jang Myeongjoong Kim Heechan Lee Seokuee Kim Bongtae Kim Geun Seog Song Su-jin Rhee Prediction of Drug–Drug Interaction Potential of Tegoprazan Using Physiologically Based Pharmacokinetic Modeling and Simulation Pharmaceutics tegoprazan physiologically based pharmacokinetics drug–drug interaction CYP3A4 potassium-competitive acid blocker |
| title | Prediction of Drug–Drug Interaction Potential of Tegoprazan Using Physiologically Based Pharmacokinetic Modeling and Simulation |
| title_full | Prediction of Drug–Drug Interaction Potential of Tegoprazan Using Physiologically Based Pharmacokinetic Modeling and Simulation |
| title_fullStr | Prediction of Drug–Drug Interaction Potential of Tegoprazan Using Physiologically Based Pharmacokinetic Modeling and Simulation |
| title_full_unstemmed | Prediction of Drug–Drug Interaction Potential of Tegoprazan Using Physiologically Based Pharmacokinetic Modeling and Simulation |
| title_short | Prediction of Drug–Drug Interaction Potential of Tegoprazan Using Physiologically Based Pharmacokinetic Modeling and Simulation |
| title_sort | prediction of drug drug interaction potential of tegoprazan using physiologically based pharmacokinetic modeling and simulation |
| topic | tegoprazan physiologically based pharmacokinetics drug–drug interaction CYP3A4 potassium-competitive acid blocker |
| url | https://www.mdpi.com/1999-4923/13/9/1489 |
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