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Clinical assessment of gepotidacin (GSK2140944) as a victim and perpetrator of drug–drug interactions via CYP3A metabolism and transporters

Gepotidacin is a novel triazaacenaphthylene antibiotic in phase III development. Based on nonclinical in vitro characterization of gepotidacin metabolism, two phase I studies were conducted in healthy participants to investigate clinical drug–drug interactions (DDIs). We assessed gepotidacin as a DD...

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Autores principales: Barth, Aline, Perry, Caroline R., Shabbir, Shaila, Zamek‐Gliszczynski, Maciej J., Thomas, Sebin, Dumont, Etienne F., Brimhall, Darin B., Nguyen, Dung, Srinivasan, Meenakshi, Swift, Brandon
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10087077/
https://www.ncbi.nlm.nih.gov/pubmed/36642822
http://dx.doi.org/10.1111/cts.13477
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author Barth, Aline
Perry, Caroline R.
Shabbir, Shaila
Zamek‐Gliszczynski, Maciej J.
Thomas, Sebin
Dumont, Etienne F.
Brimhall, Darin B.
Nguyen, Dung
Srinivasan, Meenakshi
Swift, Brandon
author_facet Barth, Aline
Perry, Caroline R.
Shabbir, Shaila
Zamek‐Gliszczynski, Maciej J.
Thomas, Sebin
Dumont, Etienne F.
Brimhall, Darin B.
Nguyen, Dung
Srinivasan, Meenakshi
Swift, Brandon
author_sort Barth, Aline
collection PubMed
description Gepotidacin is a novel triazaacenaphthylene antibiotic in phase III development. Based on nonclinical in vitro characterization of gepotidacin metabolism, two phase I studies were conducted in healthy participants to investigate clinical drug–drug interactions (DDIs). We assessed gepotidacin as a DDI victim with a potent cytochrome P450 (CYP) 3A4/P‐glycoprotein (P‐gp) inhibitor (itraconazole), potent CYP3A4 inducer (rifampicin), and nonspecific organic cation transporter (OCT)/multidrug and toxic extrusion transporter (MATE) renal transport inhibitor (cimetidine) via single doses of gepotidacin before and after co‐administration with multiple doses of the modulator drugs. Gepotidacin DDI perpetrator potential for P‐gp inhibition (digoxin) and CYP3A4 inhibition (midazolam) was evaluated via single doses of the two‐drug cocktail without and with gepotidacin. The DDI magnitudes were interpreted based on area under the concentration‐time curve (AUC). A weak DDI (AUC increase 48%–50%) was observed for gepotidacin co‐administered with itraconazole. A clinically significant decrease in gepotidacin plasma AUC (52%) was observed with rifampicin coadministration, indicating a moderate DDI. There was no DDI for gepotidacin with cimetidine; a unique biomarker approach showed increased serum creatinine (24%), decreased renal clearance of creatinine (21%), and N1‐methylnicotinamide (39%), which confirmed extensive MATE inhibition and partial OCT2 inhibition. Gepotidacin was not a P‐gp DDI perpetrator, although the maximum plasma concentration of digoxin increased (53%) and is potentially clinically relevant given its narrow therapeutic index. Gepotidacin demonstrated weak CYP3A4 inhibition with midazolam (<2‐fold AUC increase). There were no new safety‐risk profile findings. These results will inform the safe and efficacious clinical use of gepotidacin when co‐administered with other drugs.
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spelling pubmed-100870772023-04-12 Clinical assessment of gepotidacin (GSK2140944) as a victim and perpetrator of drug–drug interactions via CYP3A metabolism and transporters Barth, Aline Perry, Caroline R. Shabbir, Shaila Zamek‐Gliszczynski, Maciej J. Thomas, Sebin Dumont, Etienne F. Brimhall, Darin B. Nguyen, Dung Srinivasan, Meenakshi Swift, Brandon Clin Transl Sci Research Gepotidacin is a novel triazaacenaphthylene antibiotic in phase III development. Based on nonclinical in vitro characterization of gepotidacin metabolism, two phase I studies were conducted in healthy participants to investigate clinical drug–drug interactions (DDIs). We assessed gepotidacin as a DDI victim with a potent cytochrome P450 (CYP) 3A4/P‐glycoprotein (P‐gp) inhibitor (itraconazole), potent CYP3A4 inducer (rifampicin), and nonspecific organic cation transporter (OCT)/multidrug and toxic extrusion transporter (MATE) renal transport inhibitor (cimetidine) via single doses of gepotidacin before and after co‐administration with multiple doses of the modulator drugs. Gepotidacin DDI perpetrator potential for P‐gp inhibition (digoxin) and CYP3A4 inhibition (midazolam) was evaluated via single doses of the two‐drug cocktail without and with gepotidacin. The DDI magnitudes were interpreted based on area under the concentration‐time curve (AUC). A weak DDI (AUC increase 48%–50%) was observed for gepotidacin co‐administered with itraconazole. A clinically significant decrease in gepotidacin plasma AUC (52%) was observed with rifampicin coadministration, indicating a moderate DDI. There was no DDI for gepotidacin with cimetidine; a unique biomarker approach showed increased serum creatinine (24%), decreased renal clearance of creatinine (21%), and N1‐methylnicotinamide (39%), which confirmed extensive MATE inhibition and partial OCT2 inhibition. Gepotidacin was not a P‐gp DDI perpetrator, although the maximum plasma concentration of digoxin increased (53%) and is potentially clinically relevant given its narrow therapeutic index. Gepotidacin demonstrated weak CYP3A4 inhibition with midazolam (<2‐fold AUC increase). There were no new safety‐risk profile findings. These results will inform the safe and efficacious clinical use of gepotidacin when co‐administered with other drugs. John Wiley and Sons Inc. 2023-01-23 /pmc/articles/PMC10087077/ /pubmed/36642822 http://dx.doi.org/10.1111/cts.13477 Text en © 2023 GSK. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics. https://creativecommons.org/licenses/by-nc/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
spellingShingle Research
Barth, Aline
Perry, Caroline R.
Shabbir, Shaila
Zamek‐Gliszczynski, Maciej J.
Thomas, Sebin
Dumont, Etienne F.
Brimhall, Darin B.
Nguyen, Dung
Srinivasan, Meenakshi
Swift, Brandon
Clinical assessment of gepotidacin (GSK2140944) as a victim and perpetrator of drug–drug interactions via CYP3A metabolism and transporters
title Clinical assessment of gepotidacin (GSK2140944) as a victim and perpetrator of drug–drug interactions via CYP3A metabolism and transporters
title_full Clinical assessment of gepotidacin (GSK2140944) as a victim and perpetrator of drug–drug interactions via CYP3A metabolism and transporters
title_fullStr Clinical assessment of gepotidacin (GSK2140944) as a victim and perpetrator of drug–drug interactions via CYP3A metabolism and transporters
title_full_unstemmed Clinical assessment of gepotidacin (GSK2140944) as a victim and perpetrator of drug–drug interactions via CYP3A metabolism and transporters
title_short Clinical assessment of gepotidacin (GSK2140944) as a victim and perpetrator of drug–drug interactions via CYP3A metabolism and transporters
title_sort clinical assessment of gepotidacin (gsk2140944) as a victim and perpetrator of drug–drug interactions via cyp3a metabolism and transporters
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10087077/
https://www.ncbi.nlm.nih.gov/pubmed/36642822
http://dx.doi.org/10.1111/cts.13477
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