Applied physiologically‐based pharmacokinetic modeling to assess uridine diphosphate‐glucuronosyltransferase‐mediated drug–drug interactions for Vericiguat
Abstract Vericiguat (Verquvo; US: Merck, other countries: Bayer) is a novel drug for the treatment of chronic heart failure. Preclinical studies have demonstrated that the primary route of metabolism for vericiguat is glucuronidation, mainly catalyzed by uridine diphosphate‐glucuronosyltransferase (...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2024-01-01
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| Series: | CPT: Pharmacometrics & Systems Pharmacology |
| Online Access: | https://doi.org/10.1002/psp4.13059 |
| _version_ | 1797356293039587328 |
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| author | Sebastian Frechen Ibrahim Ince André Dallmann Michael Gerisch Natalia A. Jungmann Corina Becker Maximilian Lobmeyer Maria E. Trujillo Shiyao Xu Rolf Burghaus Michaela Meyer |
| author_facet | Sebastian Frechen Ibrahim Ince André Dallmann Michael Gerisch Natalia A. Jungmann Corina Becker Maximilian Lobmeyer Maria E. Trujillo Shiyao Xu Rolf Burghaus Michaela Meyer |
| author_sort | Sebastian Frechen |
| collection | DOAJ |
| description | Abstract Vericiguat (Verquvo; US: Merck, other countries: Bayer) is a novel drug for the treatment of chronic heart failure. Preclinical studies have demonstrated that the primary route of metabolism for vericiguat is glucuronidation, mainly catalyzed by uridine diphosphate‐glucuronosyltransferase (UGT)1A9 and to a lesser extent UGT1A1. Whereas a drug–drug interaction (DDI) study of the UGT1A9 inhibitor mefenamic acid showed a 20% exposure increase, the effect of UGT1A1 inhibitors has not been assessed clinically. This modeling study describes a physiologically‐based pharmacokinetic (PBPK) approach to complement the clinical DDI liability assessment and support prescription labeling. A PBPK model of vericiguat was developed based on in vitro and clinical data, verified against data from the mefenamic acid DDI study, and applied to assess the UGT1A1 DDI liability by running an in silico DDI study with the UGT1A1 inhibitor atazanavir. A minor effect with an area under the plasma concentration‐time curve (AUC) ratio of 1.12 and a peak plasma concentration ratio of 1.04 was predicted, which indicates that there is no clinically relevant DDI interaction anticipated. Additionally, the effect of potential genetic polymorphisms of UGT1A1 and UGT1A9 was evaluated, which showed that an average modest increase of up to 1.7‐fold in AUC may be expected in the case of concomitantly reduced UGT1A1 and UGT1A9 activity for subpopulations expressing non‐wild‐type variants for both isoforms. This study is a first cornerstone to qualify the PK‐Sim platform for use of UGT‐mediated DDI predictions, including PBPK models of perpetrators, such as mefenamic acid and atazanavir, and sensitive UGT substrates, such as dapagliflozin and raltegravir. |
| first_indexed | 2024-03-08T14:24:32Z |
| format | Article |
| id | doaj.art-c66c5343a35c4c0781974a7a44021a40 |
| institution | Directory Open Access Journal |
| issn | 2163-8306 |
| language | English |
| last_indexed | 2024-03-08T14:24:32Z |
| publishDate | 2024-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | CPT: Pharmacometrics & Systems Pharmacology |
| spelling | doaj.art-c66c5343a35c4c0781974a7a44021a402024-01-13T08:07:57ZengWileyCPT: Pharmacometrics & Systems Pharmacology2163-83062024-01-01131799210.1002/psp4.13059Applied physiologically‐based pharmacokinetic modeling to assess uridine diphosphate‐glucuronosyltransferase‐mediated drug–drug interactions for VericiguatSebastian Frechen0Ibrahim Ince1André Dallmann2Michael Gerisch3Natalia A. Jungmann4Corina Becker5Maximilian Lobmeyer6Maria E. Trujillo7Shiyao Xu8Rolf Burghaus9Michaela Meyer10Pharmacometrics/Modeling and Simulation, Research and Development Pharmaceuticals, Bayer AG Leverkusen GermanyPharmacometrics/Modeling and Simulation, Research and Development Pharmaceuticals, Bayer AG Leverkusen GermanyPharmacometrics/Modeling and Simulation, Research and Development Pharmaceuticals, Bayer AG Leverkusen GermanyDMPK, Research and Development Pharmaceuticals, Bayer AG Leverkusen GermanyDMPK, Research and Development Pharmaceuticals, Bayer AG Leverkusen GermanyClinical Pharmacology, Research and Development Pharmaceuticals, Bayer AG Leverkusen GermanyClinical Pharmacology, Research and Development Pharmaceuticals, Bayer AG Leverkusen GermanyMerck & Co., Inc. Rahway New Jersey USAMerck & Co., Inc. Rahway New Jersey USAPharmacometrics/Modeling and Simulation, Research and Development Pharmaceuticals, Bayer AG Leverkusen GermanyPharmacometrics/Modeling and Simulation, Research and Development Pharmaceuticals, Bayer AG Leverkusen GermanyAbstract Vericiguat (Verquvo; US: Merck, other countries: Bayer) is a novel drug for the treatment of chronic heart failure. Preclinical studies have demonstrated that the primary route of metabolism for vericiguat is glucuronidation, mainly catalyzed by uridine diphosphate‐glucuronosyltransferase (UGT)1A9 and to a lesser extent UGT1A1. Whereas a drug–drug interaction (DDI) study of the UGT1A9 inhibitor mefenamic acid showed a 20% exposure increase, the effect of UGT1A1 inhibitors has not been assessed clinically. This modeling study describes a physiologically‐based pharmacokinetic (PBPK) approach to complement the clinical DDI liability assessment and support prescription labeling. A PBPK model of vericiguat was developed based on in vitro and clinical data, verified against data from the mefenamic acid DDI study, and applied to assess the UGT1A1 DDI liability by running an in silico DDI study with the UGT1A1 inhibitor atazanavir. A minor effect with an area under the plasma concentration‐time curve (AUC) ratio of 1.12 and a peak plasma concentration ratio of 1.04 was predicted, which indicates that there is no clinically relevant DDI interaction anticipated. Additionally, the effect of potential genetic polymorphisms of UGT1A1 and UGT1A9 was evaluated, which showed that an average modest increase of up to 1.7‐fold in AUC may be expected in the case of concomitantly reduced UGT1A1 and UGT1A9 activity for subpopulations expressing non‐wild‐type variants for both isoforms. This study is a first cornerstone to qualify the PK‐Sim platform for use of UGT‐mediated DDI predictions, including PBPK models of perpetrators, such as mefenamic acid and atazanavir, and sensitive UGT substrates, such as dapagliflozin and raltegravir.https://doi.org/10.1002/psp4.13059 |
| spellingShingle | Sebastian Frechen Ibrahim Ince André Dallmann Michael Gerisch Natalia A. Jungmann Corina Becker Maximilian Lobmeyer Maria E. Trujillo Shiyao Xu Rolf Burghaus Michaela Meyer Applied physiologically‐based pharmacokinetic modeling to assess uridine diphosphate‐glucuronosyltransferase‐mediated drug–drug interactions for Vericiguat CPT: Pharmacometrics & Systems Pharmacology |
| title | Applied physiologically‐based pharmacokinetic modeling to assess uridine diphosphate‐glucuronosyltransferase‐mediated drug–drug interactions for Vericiguat |
| title_full | Applied physiologically‐based pharmacokinetic modeling to assess uridine diphosphate‐glucuronosyltransferase‐mediated drug–drug interactions for Vericiguat |
| title_fullStr | Applied physiologically‐based pharmacokinetic modeling to assess uridine diphosphate‐glucuronosyltransferase‐mediated drug–drug interactions for Vericiguat |
| title_full_unstemmed | Applied physiologically‐based pharmacokinetic modeling to assess uridine diphosphate‐glucuronosyltransferase‐mediated drug–drug interactions for Vericiguat |
| title_short | Applied physiologically‐based pharmacokinetic modeling to assess uridine diphosphate‐glucuronosyltransferase‐mediated drug–drug interactions for Vericiguat |
| title_sort | applied physiologically based pharmacokinetic modeling to assess uridine diphosphate glucuronosyltransferase mediated drug drug interactions for vericiguat |
| url | https://doi.org/10.1002/psp4.13059 |
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