PMID- 37470926
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20230922
IS  - 2193-8229 (Print)
IS  - 2193-6382 (Electronic)
IS  - 2193-6382 (Linking)
VI  - 12
IP  - 8
DP  - 2023 Aug
TI  - 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.
PG  - 2057-2070
LID - 10.1007/s40121-023-00830-0 [doi]
AB  - 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 microg/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.
CI  - (c) 2023. The Author(s).
FAU - Mukherjee, Dwaipayan
AU  - Mukherjee D
AUID- ORCID: 0000-0002-3918-3188
AD  - AbbVie Inc., North Chicago, IL, USA. dwaipayan.mukherjee@abbvie.com.
FAU - Collins, Michelle
AU  - Collins M
AD  - AbbVie Inc., North Chicago, IL, USA.
FAU - Dylla, Douglas E
AU  - Dylla DE
AD  - AbbVie Inc., North Chicago, IL, USA.
FAU - Kaur, Jatinder
AU  - Kaur J
AD  - AbbVie Inc., North Chicago, IL, USA.
FAU - Semizarov, Dimitri
AU  - Semizarov D
AD  - AbbVie Inc., North Chicago, IL, USA.
FAU - Martinez, Anthony
AU  - Martinez A
AD  - Jacobs School of Medicine, University at Buffalo, Buffalo, NY, USA.
FAU - Conway, Brian
AU  - Conway B
AD  - Vancouver Infectious Diseases Centre, Vancouver, Canada.
AD  - Simon Fraser University, Burnaby, Canada.
FAU - Khan, Tipu
AU  - Khan T
AD  - Ventura County Medical Center, Ventura, CA, USA.
AD  - USC Keck School of Medicine, Los Angeles, CA, USA.
FAU - Mostafa, Nael M
AU  - Mostafa NM
AD  - AbbVie Inc., North Chicago, IL, USA.
LA  - eng
PT  - Journal Article
DEP - 20230720
PL  - New Zealand
TA  - Infect Dis Ther
JT  - Infectious diseases and therapy
JID - 101634499
PMC - PMC10505123
OTO - NOTNLM
OT  - CYP3A4
OT  - Drug-drug interactions
OT  - Fentanyl
OT  - Glecaprevir
OT  - Hepatitis C virus
OT  - Opioids
OT  - Pangenotypic direct-acting antivirals
OT  - Physiologically based pharmacokinetic model
COIS- Dwaipayan Mukherjee, Michelle Collins, Douglas E. Dylla, Jatinder Kaur, Dimitri 
      Semizarov, and Nael M. Mostafa are employees of AbbVie and may hold AbbVie 
      stock/options.Anthony Martinez: speaking fees from AbbVie, Gilead, Salix, and 
      Eisai; consulting fees from AbbVie and Gilead; research grants from AbbVie, 
      Gilead, Intercept, and Allergan.Brian Conway: grants, honoraria, and research 
      support from AbbVie Inc., Gilead Sciences, Merck & Co., and ViiV Healthcare.Tipu 
      Khan: speaker, consultant, and advisory board member for AbbVie, Alkermes, and 
      Indivior.
EDAT- 2023/07/20 13:06
MHDA- 2023/07/20 13:07
PMCR- 2023/07/20
CRDT- 2023/07/20 11:13
PHST- 2023/02/27 00:00 [received]
PHST- 2023/05/23 00:00 [accepted]
PHST- 2023/07/20 13:07 [medline]
PHST- 2023/07/20 13:06 [pubmed]
PHST- 2023/07/20 11:13 [entrez]
PHST- 2023/07/20 00:00 [pmc-release]
AID - 10.1007/s40121-023-00830-0 [pii]
AID - 830 [pii]
AID - 10.1007/s40121-023-00830-0 [doi]
PST - ppublish
SO  - Infect Dis Ther. 2023 Aug;12(8):2057-2070. doi: 10.1007/s40121-023-00830-0. Epub 
      2023 Jul 20.