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

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. Supplementary Information The online version contains supplementary material available at 10.1007/s40121-023-00830-0.

GRAND PLAN: Safety and Efficacy of Glecaprevir/Pibrentasvir for the Treatment of Hepatitis C Virus Infection Among People Initially Disengaged From Health Care Who Use Drugs—A Systematic Multidisciplinary Approach

“…This has been discussed on https://www.hep-druginteractions.org/checker . However, recent data suggest that this interaction is minimal at worst and not likely to be of any clinical significance [ 15 ]. Building on an established program for engagement of inner-city residents in care, we identified 117 persons with HCV infection who were eligible to receive government-funded antiviral therapy.…”

“…The only part of our program that goes beyond this is the CPC, a weekly 3-hour event that draws on existing personnel and whose cost of operation is modest when compared with other more ambitious outreach programs that, based on their published results, have been less productive. Furthermore, the potential interaction of G/P and fentanyl is yet to be studied in the field, and this study has not encountered clinical issues or documented any increase in overdose due to this interaction [ 15 ].…”

Reported adverse events related to use of hepatitis C virus direct-acting antivirals with opioids: 2017–2021

“…Concerns related to DDIs between DAAs and opioids are predominantly around the weak CYP34A inhibitors grazoprevir and glecaprevir [ 15 ]. A recent physiologically based PK study on the coadministration of G/P with fentanyl suggested that at therapeutic doses of G/P, there is a negligible effect on the PK of IV fentanyl [ 20 ]. To date, there are no studies with EBV/GZR and fentanyl, oxycodone, or hydrocodone, but PK studies of other drugs metabolized by CYP34A, methadone, and buprenorphine/naloxone suggest there are no clinically relevant changes in exposure and no dose adjustment is required.…”