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 5 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 5 16%-48%) and 31% (range 5 22%-64%) after 1 and 2 weeks, respectively. The CSA drug clearance was reduced to 38.7% (range 5 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 Abbreviations: k, elimination rate; C 0 , adjusted number of messenger RNA transcripts at the cyclosporine A predose concentra-

Pharmacodynamic Monitoring of Ciclosporin and Tacrolimus: Insights From Nuclear Factor of Activated T-Cell–Regulated Gene Expression in Healthy Volunteers

“…In general, clinical effects of drugs are presumably driven by average exposure or by the effect–time course during a dose interval (or longer period) and not by concentration or effect at a single time point. Previous analyses of the CNI effect–time course in organ transplant patients, using the full-blood method, indicated rapid recovery of NFAT-RGE within 12 hours, 12–14,25 also shown using other assay methods, 26,27 and even higher NFAT-RGE in the evening, which might be considered as a rebound. 8,9,25 However, the relationship between individual RGE tmax , measured at the time point where the maximum concentration is typically expected, and individual average suppression of NFAT-RGE during a dose interval is unknown.…”

“…Previous analyses of the CNI effect–time course in organ transplant patients, using the full-blood method, indicated rapid recovery of NFAT-RGE within 12 hours, 12–14,25 also shown using other assay methods, 26,27 and even higher NFAT-RGE in the evening, which might be considered as a rebound. 8,9,25 However, the relationship between individual RGE tmax , measured at the time point where the maximum concentration is typically expected, and individual average suppression of NFAT-RGE during a dose interval is unknown. This relationship is difficult to analyze in patients because baseline NFAT-RGEs (ie, without any CNI) cannot be obtained in transplant patients treated with CNIs.…”

Daily Low-dose Tacrolimus Is a Safe and Effective Immunosuppressive Regimen During Telaprevir-based Triple Therapy for Hepatitis C Virus Recurrence After Liver Transplant

“…This approach is further encouraged by a recent report showing that immunosuppressive effects of CyA might be reduced during telaprevir therapy because of an increase of nuclear factor of activated T-cells-regulated genes. 13 The often-mentioned limitations of poor controllability of TAC concentrations (because of the significantly extended half-lives of immunosuppressants) during HCV therapy with PIs 14 can be overcome by the scheme of administration described here. The dose reduction factor for TAC in our cohort was substantial (30-fold).…”