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

Dwaipayan Mukherjee; Michelle Collins; Douglas E Dylla; Jatinder Kaur; Dimitri Semizarov; Anthony Martinez; Brian Conway; Tipu Khan; Nael M Mostafa

doi:10.1007/s40121-023-00830-0

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

Infect Dis Ther. 2023 Aug;12(8):2057-2070. doi: 10.1007/s40121-023-00830-0. Epub 2023 Jul 20.

Authors

Affiliations

¹ AbbVie Inc., North Chicago, IL, USA. dwaipayan.mukherjee@abbvie.com.
² AbbVie Inc., North Chicago, IL, USA.
³ Jacobs School of Medicine, University at Buffalo, Buffalo, NY, USA.
⁴ Vancouver Infectious Diseases Centre, Vancouver, Canada.
⁵ Simon Fraser University, Burnaby, Canada.
⁶ Ventura County Medical Center, Ventura, CA, USA.
⁷ USC Keck School of Medicine, Los Angeles, CA, USA.

Abstract

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.

Keywords: CYP3A4; Drug–drug interactions; Fentanyl; Glecaprevir; Hepatitis C virus; Opioids; Pangenotypic direct-acting antivirals; Physiologically based pharmacokinetic model.