title: Decreased tacrolimus plasma concentrations during HCV therapy: a drug-drug interaction or is there an alternative explanation?
abstract: Chronic hepatitis C virus (HCV) infection can cause severe liver cirrhosis, for which liver transplantation is the only therapy. To prevent organ rejection, transplanted patients are treated with immunosuppressive agents. We describe two transplanted patients treated with tacrolimus who were simultaneously treated with direct-acting antivirals (DAAs) for their chronic HCV infection. No pharmacokinetic drug-drug interactions (DDIs) were expected between tacrolimus and the selected DAAs. However, in both patients, tacrolimus plasma concentrations decreased during HCV treatment. We hypothesise that decreased plasma concentrations were not caused by a DDI but were an indirect result of the clearance of the HCV infection. During chronic HCV infection, pro-inflammatory cytokines may inhibit cytochrome P450 (CYP) enzymes, which are primarily responsible for tacrolimus metabolism. If this is true, then with clearance of the virus the activity of these enzymes will normalise and tacrolimus metabolism will increase. These changes were clinically relevant because the tacrolimus dosage needed to be adjusted. Therefore, physicians should be aware that CYP substrates with narrow therapeutic ranges might require dose adaption during HCV therapy with DAAs.
authors.affiliation: Department of Pharmacy, radboud university medical center, Geert Grooteplein Zuid 10, 6525 GA Nijmegen, The Netherlands. Electronic address: Elise.Smolders@radboudumc.nl.
authors.forename: E J
authors.initials: EJ
authors.lastname: Smolders
authors.affiliation: Department of Gastroenterology and Hepatology, radboud university medical center, Nijmegen, The Netherlands.
authors.forename: S
authors.initials: S
authors.lastname: Pape
authors.affiliation: Department of Pharmacy, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: C T M M
authors.initials: CT
authors.lastname: de Kanter
authors.affiliation: Department of Gastroenterology and Hepatology, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: A P
authors.initials: AP
authors.lastname: van den Berg
authors.affiliation: Department of Gastroenterology and Hepatology, radboud university medical center, Nijmegen, The Netherlands.
authors.forename: J P H
authors.initials: JP
authors.lastname: Drenth
authors.affiliation: Department of Pharmacy, radboud university medical center, Geert Grooteplein Zuid 10, 6525 GA Nijmegen, The Netherlands.
authors.forename: D M
authors.initials: DM
authors.lastname: Burger
mesh_terms: D000368:Aged; D000998:Antiviral Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004347:Drug Interactions; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000601:surgery; D006801:Humans; D007166:Immunosuppressive Agents / Q000097:blood* / Q000493:pharmacokinetics; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D010949:Plasma / Q000737:chemistry*; D016559:Tacrolimus / Q000097:blood* / Q000493:pharmacokinetics; D066027:Transplant Recipients
chemical_list: D000998:Antiviral Agents; D007166:Immunosuppressive Agents; D003577:Cytochrome P-450 Enzyme System; D016559:Tacrolimus
keywords: CYP3A4; Direct-acting antiviral; HCV; Hepatitis C virus; Tacrolimus