title: Pharmacodynamic monitoring of immunosuppressive effects indicates reduced cyclosporine activity during telaprevir therapy.
abstract: Drug interactions with immunosuppressive drugs are a major problem associated with protease inhibitor-based antiviral triple therapy for hepatitis C virus (HCV) reinfection after liver transplantation. In this retrospective cohort study, we analyzed biomarkers of the immunosuppressive effects of cyclosporine A (CSA) by quantifying nuclear factor of activated T cells (NFAT)-regulated gene expression during telaprevir (TVR) therapy in 5 liver transplant patients. Furthermore, dose adjustments and blood concentrations of CSA as well as the clinical course were analyzed. We observed a clear impact of TVR not only on doses and blood concentrations but also on the immunosuppressive effects of CSA. Despite apparently adequate CSA trough concentrations, the CSA peak concentration decreased to 68% (range = 44%-90%). This was associated with a 1.9-fold (1.6- to 4.1-fold) increase in the residual gene activity of NFAT-regulated genes, which indicated reduced immunosuppressive activity of CSA with TVR co-medication. The median dose of CSA was reduced to 25% (range = 16%-48%) and 31% (range = 22%-64%) after 1 and 2 weeks, respectively. The CSA drug clearance was reduced to 38.7% (range = 31.0%-49.4%). We report excellent antiviral efficacy. At the end of the observation period, all patients were HCV RNA-negative (1 patient at 18 weeks, 1 patient at 12 weeks, and 3 patients at 4 weeks after the end of therapy). Safety was acceptable, with mild acute rejection and reactivation of cytomegalovirus being the most serious adverse events. One patient with histologically proven recurrent cholestatic hepatitis before therapy underwent retransplantation during the course of antiviral therapy. In conclusion, the immunomonitoring of NFAT-regulated gene expression indicated reduced immunosuppressive activity of CSA during antiviral therapy with TVR in our cohort of liver transplant patients. Thus, the immunosuppressive effects of CSA may be overestimated if one is looking only at trough concentrations during co-medication with protease inhibitors or other strong cytochrome P450 3A inhibitors. Immunomonitoring of NFAT-regulated gene expression could, therefore, help to prevent overimmunosuppression or underimmunosuppression.
authors.affiliation: Departments of Gastroenterology, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Roos
authors.forename: Daniel
authors.initials: D
authors.lastname: Gotthardt
authors.forename: Thomas
authors.initials: T
authors.lastname: Giese
authors.forename: Paul
authors.initials: P
authors.lastname: Schnitzler
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Stremmel
authors.forename: David
authors.initials: D
authors.lastname: Czock
authors.forename: Christoph
authors.initials: C
authors.lastname: Eisenbach
mesh_terms: D000998:Antiviral Agents / Q000009:adverse effects / Q000627:therapeutic use; D015415:Biomarkers / Q000097:blood; D016572:Cyclosporine / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004306:Dose-Response Relationship, Immunologic; D004347:Drug Interactions; D016903:Drug Monitoring / Q000379:methods*; D058625:End Stage Liver Disease / Q000175:diagnosis / Q000601:surgery* / Q000821:virology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics; D016174:Hepacivirus / Q000187:drug effects / Q000235:genetics; D006526:Hepatitis C / Q000150:complications / Q000175:diagnosis / Q000188:drug therapy*; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D007371:Interferon-gamma / Q000235:genetics; D007376:Interleukin-2 / Q000235:genetics; D016031:Liver Transplantation / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D009842:Oligopeptides / Q000009:adverse effects / Q000627:therapeutic use*; D011237:Predictive Value of Tests; D012333:RNA, Messenger / Q000097:blood; D012367:RNA, Viral / Q000097:blood; D012008:Recurrence; D012189:Retrospective Studies; D013997:Time Factors; D016896:Treatment Outcome; D019562:Viral Load
chemical_list: D000998:Antiviral Agents; D015415:Biomarkers; C573415:IFNG protein, human; C508594:IL2 protein, human; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D009842:Oligopeptides; D012333:RNA, Messenger; D012367:RNA, Viral; C486464:telaprevir; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D016572:Cyclosporine