Assessment of Drug-Drug Interaction Risk Between Intravenous Fentanyl and the Glecaprevir/Pibrentasvir Combination Regimen in Hepatitis C Patients Using Physiologically Based Pharmacokinetic Modeling and Simulations
© 2023. The Author(s)..
INTRODUCTION: An unsafe injection practice is one of the major contributors to new hepatitis C virus (HCV) infections; thus, people who inject drugs are a key population to prioritize to achieve HCV elimination. The introduction of highly effective and well-tolerated pangenotypic direct-acting antivirals, including glecaprevir/pibrentasvir (GLE/PIB), has revolutionized the HCV treatment landscape. Glecaprevir is a weak cytochrome P450 3A4 (CYP3A4) inhibitor, so there is the potential for drug-drug interactions (DDIs) with some opioids metabolized by CYP3A4, such as fentanyl. This study estimated the impact of GLE/PIB on the pharmacokinetics of intravenous fentanyl by building a physiologically based pharmacokinetic (PBPK) model.
METHODS: A PBPK model was developed for intravenous fentanyl by incorporating published information on fentanyl metabolism, distribution, and elimination in healthy individuals. Three clinical DDI studies were used to verify DDIs within the fentanyl PBPK model. This model was integrated with a previously developed GLE/PIB PBPK model. After model validation, DDI simulations were conducted by coadministering GLE 300 mg + PIB 120 mg with a single dose of intravenous fentanyl (0.5 µg/kg).
RESULTS: The predicted maximum plasma concentration ratio between GLE/PIB + fentanyl and fentanyl alone was 1.00, and the predicted area under the curve ratio was 1.04, suggesting an increase of only 4% in fentanyl exposure.
CONCLUSION: The administration of a therapeutic dose of GLE/PIB has very little effect on the pharmacokinetics of intravenous fentanyl. This negligible increase would not be expected to increase the risk of fentanyl overdose beyond the inherent risks related to the amount and purity of the fentanyl received during recreational use.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:12 |
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| Enthalten in: |
Infectious diseases and therapy - 12(2023), 8 vom: 20. Aug., Seite 2057-2070 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Mukherjee, Dwaipayan [VerfasserIn] |
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| Links: |
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| Themen: |
CYP3A4 |
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| Anmerkungen: |
Date Revised 22.09.2023 published: Print-Electronic Citation Status PubMed-not-MEDLINE |
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| doi: |
10.1007/s40121-023-00830-0 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM359713777 |
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| 100 | 1 | |a Mukherjee, Dwaipayan |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Assessment of Drug-Drug Interaction Risk Between Intravenous Fentanyl and the Glecaprevir/Pibrentasvir Combination Regimen in Hepatitis C Patients Using Physiologically Based Pharmacokinetic Modeling and Simulations |
| 264 | 1 | |c 2023 | |
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| 500 | |a Date Revised 22.09.2023 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status PubMed-not-MEDLINE | ||
| 520 | |a © 2023. The Author(s). | ||
| 520 | |a INTRODUCTION: An unsafe injection practice is one of the major contributors to new hepatitis C virus (HCV) infections; thus, people who inject drugs are a key population to prioritize to achieve HCV elimination. The introduction of highly effective and well-tolerated pangenotypic direct-acting antivirals, including glecaprevir/pibrentasvir (GLE/PIB), has revolutionized the HCV treatment landscape. Glecaprevir is a weak cytochrome P450 3A4 (CYP3A4) inhibitor, so there is the potential for drug-drug interactions (DDIs) with some opioids metabolized by CYP3A4, such as fentanyl. This study estimated the impact of GLE/PIB on the pharmacokinetics of intravenous fentanyl by building a physiologically based pharmacokinetic (PBPK) model | ||
| 520 | |a METHODS: A PBPK model was developed for intravenous fentanyl by incorporating published information on fentanyl metabolism, distribution, and elimination in healthy individuals. Three clinical DDI studies were used to verify DDIs within the fentanyl PBPK model. This model was integrated with a previously developed GLE/PIB PBPK model. After model validation, DDI simulations were conducted by coadministering GLE 300 mg + PIB 120 mg with a single dose of intravenous fentanyl (0.5 µg/kg) | ||
| 520 | |a RESULTS: The predicted maximum plasma concentration ratio between GLE/PIB + fentanyl and fentanyl alone was 1.00, and the predicted area under the curve ratio was 1.04, suggesting an increase of only 4% in fentanyl exposure | ||
| 520 | |a CONCLUSION: The administration of a therapeutic dose of GLE/PIB has very little effect on the pharmacokinetics of intravenous fentanyl. This negligible increase would not be expected to increase the risk of fentanyl overdose beyond the inherent risks related to the amount and purity of the fentanyl received during recreational use | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a CYP3A4 | |
| 650 | 4 | |a Drug–drug interactions | |
| 650 | 4 | |a Fentanyl | |
| 650 | 4 | |a Glecaprevir | |
| 650 | 4 | |a Hepatitis C virus | |
| 650 | 4 | |a Opioids | |
| 650 | 4 | |a Pangenotypic direct-acting antivirals | |
| 650 | 4 | |a Physiologically based pharmacokinetic model | |
| 700 | 1 | |a Collins, Michelle |e verfasserin |4 aut | |
| 700 | 1 | |a Dylla, Douglas E |e verfasserin |4 aut | |
| 700 | 1 | |a Kaur, Jatinder |e verfasserin |4 aut | |
| 700 | 1 | |a Semizarov, Dimitri |e verfasserin |4 aut | |
| 700 | 1 | |a Martinez, Anthony |e verfasserin |4 aut | |
| 700 | 1 | |a Conway, Brian |e verfasserin |4 aut | |
| 700 | 1 | |a Khan, Tipu |e verfasserin |4 aut | |
| 700 | 1 | |a Mostafa, Nael M |e verfasserin |4 aut | |
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