Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2023 Oct;62(10):1365-1392.
doi: 10.1007/s40262-023-01302-x. Epub 2023 Sep 20.

Mechanisms and Clinical Significance of Pharmacokinetic Drug Interactions Mediated by FDA and EMA-approved Hepatitis C Direct-Acting Antiviral Agents

Michael Murray  1
Affiliations
Review

Mechanisms and Clinical Significance of Pharmacokinetic Drug Interactions Mediated by FDA and EMA-approved Hepatitis C Direct-Acting Antiviral Agents

Michael Murray. Clin Pharmacokinet. 2023 Oct.

Abstract

The treatment of patients infected with the hepatitis C virus (HCV) has been revolutionised by the development of direct-acting antiviral agents (DAAs) that target specific HCV proteins involved in viral replication. The first DAAs were associated with clinical problems such as adverse drug reactions and pharmacokinetic drug-drug interactions (DDIs). Current FDA/EMA-approved treatments are combinations of DAAs that simultaneously target the HCV N5A-protein, the HCV N5B-polymerase and the HCV NS3/4A-protease. Adverse events and DDIs are less likely with these DAA combinations but several DDIs of potential clinical significance remain. Much of the available information on the interaction of DAAs with CYP drug-metabolising enzymes and influx and efflux transporters is contained in regulatory summaries and is focused on DDIs of likely clinical importance. Important DDIs perpetrated by current DAAs include increases in the pharmacokinetic exposure to statins and dabigatran. Some mechanistic information can be deduced. Although the free concentrations of DAAs in serum are very low, a number of these DDIs are likely mediated by the inhibition of systemic influx transporters, especially OATP1B1/1B3. Other DDIs may arise by DAA-mediated inhibition of intestinal efflux transporters, which increases the systemic concentrations of some coadministered drugs. Conversely, DAAs are victims of DDIs mediated by cyclosporin, ketoconazole, omeprazole and HIV antiretroviral drug combinations, especially when boosted by ritonavir and, to a lesser extent, cobicistat. In addition, concurrent administration of inducers, such as rifampicin, carbamazepine and efavirenz, decreases exposure to some DAAs. Drug-drug interactions that increase the accumulation of HCV N3/4A-protease inhibitors like grazoprevir may exacerbate hepatic injury in HCV patients.

Plain language summary

Direct-acting antiviral (DAA) drugs have revolutionised the treatment of patients with hepatitis C. Compared to the earlier agents, currently-approved DAA combinations have fewer adverse effects and are less likely to be associated with pharmacokinetic drug-drug interactions (DDIs). However, adverse events and DDIs still occur when DAAs are coadministered with certain drugs. In most cases DAAs likely perpetrate DDIs by inhibiting drug transporters. However, access to more detailed information on HCV DAAs as substrates and inhibitors of drug-metabolising enzymes and transporters, and the incidence of DDIs in target populations, would enhance the understanding of the significance of the likelihood of DDIs with DAAs.

PubMed Disclaimer

Similar articles

See all similar articles

Cited by

References

    1. Petruzziello A, Marigliano S, Loquercio G, Cozzolino A, Cacciapuoti C. Global epidemiology of hepatitis C virus infection: An up-date of the distribution and circulation of hepatitis C virus genotypes. World J Gastroenterol. 2016;22:7824–40. https://doi.org/10.3748/wjg.v22.i34.7824 . - DOI - PubMed - PMC
    1. Lanini S, Easterbrook PJ, Zumla A, Ippolito G. Hepatitis C: global epidemiology and strategies for control. Clin Microbiol Infect. 2016;22:833–8. https://doi.org/10.1016/j.cmi.2016.07.035 . - DOI - PubMed
    1. Cacoub P, Sadoun D. Extrahepatic manifestations of chronic HCV infection. N Engl J Med. 2021;384:1038–52. https://doi.org/10.1056/NEJMra2033539 . - DOI - PubMed
    1. Zappulo E, Scotto R, Buonomo AR, Maraolo AE, Pinchera B, Gentile I. Efficacy and safety of a fixed dose combination tablet of asunaprevir + beclabuvir + daclatasvir for the treatment of Hepatitis C. Exp Opin Pharmacother. 2020;21:261–73. https://doi.org/10.1080/14656566.2019.1697674 . - DOI
    1. Dubuisson J. Hepatitis C virus proteins. World J Gastroenterol. 2007;13:2406–15. https://doi.org/10.3748/wjg.v13.i17.2406 . - DOI - PubMed - PMC

Substances

LinkOut - more resources