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A Physiologically Based Pharmacokinetic Model of Ketoconazole and Its Metabolites as Drug–Drug Interaction Perpetrators

The antifungal ketoconazole, which is mainly used for dermal infections and treatment of Cushing’s syndrome, is prone to drug–food interactions (DFIs) and is well known for its strong drug–drug interaction (DDI) potential. Some of ketoconazole’s potent inhibitory activity can be attributed to its me...

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Autores principales: Marok, Fatima Zahra, Wojtyniak, Jan-Georg, Fuhr, Laura Maria, Selzer, Dominik, Schwab, Matthias, Weiss, Johanna, Haefeli, Walter Emil, Lehr, Thorsten
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9965990/
https://www.ncbi.nlm.nih.gov/pubmed/36840001
http://dx.doi.org/10.3390/pharmaceutics15020679
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author Marok, Fatima Zahra
Wojtyniak, Jan-Georg
Fuhr, Laura Maria
Selzer, Dominik
Schwab, Matthias
Weiss, Johanna
Haefeli, Walter Emil
Lehr, Thorsten
author_facet Marok, Fatima Zahra
Wojtyniak, Jan-Georg
Fuhr, Laura Maria
Selzer, Dominik
Schwab, Matthias
Weiss, Johanna
Haefeli, Walter Emil
Lehr, Thorsten
author_sort Marok, Fatima Zahra
collection PubMed
description The antifungal ketoconazole, which is mainly used for dermal infections and treatment of Cushing’s syndrome, is prone to drug–food interactions (DFIs) and is well known for its strong drug–drug interaction (DDI) potential. Some of ketoconazole’s potent inhibitory activity can be attributed to its metabolites that predominantly accumulate in the liver. This work aimed to develop a whole-body physiologically based pharmacokinetic (PBPK) model of ketoconazole and its metabolites for fasted and fed states and to investigate the impact of ketoconazole’s metabolites on its DDI potential. The parent–metabolites model was developed with PK-Sim(®) and MoBi(®) using 53 plasma concentration-time profiles. With 7 out of 7 (7/7) DFI AUC(last) and DFI C(max) ratios within two-fold of observed ratios, the developed model demonstrated good predictive performance under fasted and fed conditions. DDI scenarios that included either the parent alone or with its metabolites were simulated and evaluated for the victim drugs alfentanil, alprazolam, midazolam, triazolam, and digoxin. DDI scenarios that included all metabolites as reversible inhibitors of CYP3A4 and P-gp performed best: 26/27 of DDI AUC(last) and 21/21 DDI C(max) ratios were within two-fold of observed ratios, while DDI models that simulated only ketoconazole as the perpetrator underperformed: 12/27 DDI AUC(last) and 18/21 DDI C(max) ratios were within the success limits.
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spelling pubmed-99659902023-02-26 A Physiologically Based Pharmacokinetic Model of Ketoconazole and Its Metabolites as Drug–Drug Interaction Perpetrators Marok, Fatima Zahra Wojtyniak, Jan-Georg Fuhr, Laura Maria Selzer, Dominik Schwab, Matthias Weiss, Johanna Haefeli, Walter Emil Lehr, Thorsten Pharmaceutics Article The antifungal ketoconazole, which is mainly used for dermal infections and treatment of Cushing’s syndrome, is prone to drug–food interactions (DFIs) and is well known for its strong drug–drug interaction (DDI) potential. Some of ketoconazole’s potent inhibitory activity can be attributed to its metabolites that predominantly accumulate in the liver. This work aimed to develop a whole-body physiologically based pharmacokinetic (PBPK) model of ketoconazole and its metabolites for fasted and fed states and to investigate the impact of ketoconazole’s metabolites on its DDI potential. The parent–metabolites model was developed with PK-Sim(®) and MoBi(®) using 53 plasma concentration-time profiles. With 7 out of 7 (7/7) DFI AUC(last) and DFI C(max) ratios within two-fold of observed ratios, the developed model demonstrated good predictive performance under fasted and fed conditions. DDI scenarios that included either the parent alone or with its metabolites were simulated and evaluated for the victim drugs alfentanil, alprazolam, midazolam, triazolam, and digoxin. DDI scenarios that included all metabolites as reversible inhibitors of CYP3A4 and P-gp performed best: 26/27 of DDI AUC(last) and 21/21 DDI C(max) ratios were within two-fold of observed ratios, while DDI models that simulated only ketoconazole as the perpetrator underperformed: 12/27 DDI AUC(last) and 18/21 DDI C(max) ratios were within the success limits. MDPI 2023-02-17 /pmc/articles/PMC9965990/ /pubmed/36840001 http://dx.doi.org/10.3390/pharmaceutics15020679 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Marok, Fatima Zahra
Wojtyniak, Jan-Georg
Fuhr, Laura Maria
Selzer, Dominik
Schwab, Matthias
Weiss, Johanna
Haefeli, Walter Emil
Lehr, Thorsten
A Physiologically Based Pharmacokinetic Model of Ketoconazole and Its Metabolites as Drug–Drug Interaction Perpetrators
title A Physiologically Based Pharmacokinetic Model of Ketoconazole and Its Metabolites as Drug–Drug Interaction Perpetrators
title_full A Physiologically Based Pharmacokinetic Model of Ketoconazole and Its Metabolites as Drug–Drug Interaction Perpetrators
title_fullStr A Physiologically Based Pharmacokinetic Model of Ketoconazole and Its Metabolites as Drug–Drug Interaction Perpetrators
title_full_unstemmed A Physiologically Based Pharmacokinetic Model of Ketoconazole and Its Metabolites as Drug–Drug Interaction Perpetrators
title_short A Physiologically Based Pharmacokinetic Model of Ketoconazole and Its Metabolites as Drug–Drug Interaction Perpetrators
title_sort physiologically based pharmacokinetic model of ketoconazole and its metabolites as drug–drug interaction perpetrators
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9965990/
https://www.ncbi.nlm.nih.gov/pubmed/36840001
http://dx.doi.org/10.3390/pharmaceutics15020679
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