Efficacy of C0 and C2 Monitoring in Adult Liver Transplant Recipients Treated With Neoral, Mycophenolate Mofetil, and Steroids

Treckmann, Jürgen; Paul, Andreas; Özcelik, Arzu; Saner, Fuat H.; Malagó, Massimo; Nadalin, Silvio; Lang, Hauke; Malamutman, E.; Gerken, Guido; Broelsch, Christoph E.

doi:10.1016/j.transproceed.2007.06.075

Cited by 5 publications

(4 citation statements)

References 11 publications

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“…To avoid liver graft rejection, the C 2 blood concentration was maintained at the target level. 19) On the other hand, the trough level of cyclosporine was kept low to prevent adverse effects on the kidney. 20,21) Therefore, we determined that the dosage of cyclosporine would not be 25 mg/d, but rather 50 mg/qod.…”

Section: Discussionmentioning

confidence: 99%

Successful Telaprevir Treatment in Combination of Cyclosporine against Recurrence of Hepatitis C in the Japanese Liver Transplant Patients

Kikuchi

Okuda

Ueda

et al. 2014

Biological & Pharmaceutical Bulletin

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Telaprevir (TVR) is a protease inhibitor used in combination with pegylated interferon alfa-2b and ribavirin for hepatitis C, and TVR strongly inhibits CYP3A4 and CYP3A5. We reported successful TVR treatment of liver transplant patients with recurrence of hepatitis C during receiving immunosuppressive therapy. Before initiation of triple therapy, all patients switched from tacrolimus to cyclosporine, which has a lower inhibitory effect on CYP3A4 and CYP3A5 than tacrolimus. To avoid graft failure, we measured the cyclosporine blood concentrations at 0, 2, and 6 h after administration to maintain the target level (150-200 ng/ mL) within 1 week after initiation of TVR and adjusted the dose of cyclosporine. The dose of cyclosporine was decreased 0.24-0.40 fold in all patients after initiation of TVR treatment. In 3 patients, the dose of TVR was decreased two-thirds of starting dose because of adverse effects, including anorexia and skin rash. However, the HCV RNA level rapidly decreased to undetectable levels within 1 month. Furthermore, all patients completed the TVR therapy in 12 weeks and did not experience liver graft rejection. In addition, we found the rapid elimination of inhibitory effect of TVR on the disposition of cyclospirne in the all four cases and therefore, rapid increase in the dosage of cyclosporine would be required immediately after the end of TVR administration. These results suggest that frequent measurement of cyclosporine levels was important for successful TVR triple therapy and prevention of rejection.

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Section: Discussionmentioning

confidence: 99%

Successful Telaprevir Treatment in Combination of Cyclosporine against Recurrence of Hepatitis C in the Japanese Liver Transplant Patients

Kikuchi

Okuda

Ueda

et al. 2014

Biological & Pharmaceutical Bulletin

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“… 17 , 18 Using 2-h CsA monitoring (C2) better reflects the area under the curve (AUC) and has been associated with less rejection and better renal function than C0. 17 , 23 , 24 Because of this, in previous studies in LT that compared C0 with T0, some differences may have been caused by inaccurate dosing of CsA due to trough-level monitoring. This implies that it is still unclear which CNI is superior after LT.…”

Section: Introductionmentioning

confidence: 99%

Randomized Trial of Ciclosporin with 2-h Monitoring vs. Tacrolimus with Trough Monitoring in Liver Transplantation: DELTA Study

Ruijter¹,

Inderson²,

Berg³

et al. 2023

J Clin Transl Hepatol

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Background and Aims: Previous trials comparing cyclosporine and tacrolimus after liver transplantation (LT) showed conflicting results. Most used trough monitoring for cyclosporine (C0), leading to less accurate dosing than with 2-h monitoring (C2). Only one larger trial compared C2 with tacrolimus based on trough level (T0) after LT, with similar treated biopsy-proven acute rejection (tBPAR) and graft loss, while a smaller trial had less tBPAR with C2 compared to T0. There-

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“…Indeed, a cohort study of 3 liver transplant patients treated with a different protease inhibitor (ritonavir‐boosted indinavir as part of human immunodeficiency virus therapy) reported CSA concentrations with markedly altered (flat) absorption/elimination characteristics and with more or less constant blood concentrations throughout the entire dosing interval and prolonged elimination half‐lives (up to 38 hours) . CSA peak concentrations seem to correlate with CSA immunosuppressive activity, however . Therefore, measured trough concentrations of CSA during triple therapy might not reflect the biological activity of CSA.…”

mentioning

confidence: 99%

“…15 CSA peak concentrations seem to correlate with CSA immunosuppressive activity, however. 16,17 Therefore, measured trough concentrations of CSA during triple therapy might not reflect the biological activity of CSA. Thus, patients with organ transplants might have an increased risk of organ rejection despite unchanged trough concentrations.…”

mentioning

confidence: 99%

Pharmacodynamic monitoring of immunosuppressive effects indicates reduced cyclosporine activity during telaprevir therapy

et al. 2014

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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-

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Efficacy of C0 and C2 Monitoring in Adult Liver Transplant Recipients Treated With Neoral, Mycophenolate Mofetil, and Steroids

Cited by 5 publications

References 11 publications

Successful Telaprevir Treatment in Combination of Cyclosporine against Recurrence of Hepatitis C in the Japanese Liver Transplant Patients

Successful Telaprevir Treatment in Combination of Cyclosporine against Recurrence of Hepatitis C in the Japanese Liver Transplant Patients

Randomized Trial of Ciclosporin with 2-h Monitoring vs. Tacrolimus with Trough Monitoring in Liver Transplantation: DELTA Study

Pharmacodynamic monitoring of immunosuppressive effects indicates reduced cyclosporine activity during telaprevir therapy

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