Use of Neoral C2 monitoring: a European consensus

Abstract

Summary Large‐scale clinical trials using C2 monitoring of cyclosporine (CsA) microemulsion (Neoral) in renal transplant recipients have demonstrated low acute rejection rates and good tolerability with a low adverse event profile in a variety of settings: with or without routine induction therapy; in combination with mycophenolate mofetil; with standard‐exposure or low‐exposure Neoral; and in patients with immediate or delayed graft function. In liver transplantation, C2 monitoring significantly reduces the severity and incidence of acute rejection compared with C0 monitoring, without adverse consequences in terms of renal function or tolerability. Different C2 targets are appropriate depending on adjunctive immune suppression, level of immunologic risk, CsA tolerability, risk of renal toxicity and time since transplantation. CsA absorption may increase substantially in most patients during the first 1–2 weeks post‐transplant, and this should be taken into account to avoid overshooting C2 target range. A patient with a low C2 value may be either a low or a delayed absorber of CsA, or be a normal absorber who is receiving too low a dose of Neoral. C2 monitoring alone is insufficient to differentiate between these types of patients, and measurement of additional timepoints is recommended. Adopting C2 monitoring in maintenance transplant patients identifies those who are overexposed to CsA. In summary, randomized, prospective, multicenter studies and single‐center trials have evaluated Neoral C2 monitoring within a range of regimens in different organ types, providing a robust evidence base for the benefits of this sensitive monitoring technique.

CsA 2-h concentration correlates best with area under the concentration–time curve after allo-SCT compared with trough CsA

“…Although target C2 levels have been reported, for example, in renal 33,34 and liver 34,35 transplant recipients, the significance of C2 levels in allo-SCT recipients may be complicated by interactions of CsA with other immunosuppressants. Calcineurin inhibitors may interfere with ATG-induced apoptosis of activated lymphocytes, resulting in decreased efficacy; 36 consistent with this, heart transplant patients receiving an anti-CD25 (IL-2 receptor) Ab exposed to lower C2 levels had a lower rate of graft rejection.…”

Calcineurin Inhibitor Nephrotoxicity

“…However, especially for cyclosporine, there is only a poor correlation between C 0 levels and total exposure (measured as area under the time-concentration curve; AUC 0 to 12 ). Monitoring of cyclosporine levels 2 h after administration (C 2 ) appeared to be the single time point that correlates best with total exposure (251,252), and could offer additional benefit over C 0 (253). Application of C 2 monitoring is, however, more complicated than C 0 monitoring, and there are no conclusive direct studies showing a significant benefit of C 2 over C 0 monitoring, which is a main reason most centers still rely on C 0 monitoring for cyclosporine (249,254).…”

Cyclosporine A (CsA) 2-h concentrations vary between patients without correlation to graft-versus-host disease after allogeneic haematopoietic stem cell transplantation

“…13,26,27 Different C2 target concentrations have been suggested in different solid organ transplantation settings, varying between 1400 and 1600 ng/ ml early after renal transplantation to 400 and 600 ng/ml in 2-h cyclosporine A concentration L Barkholt et al stable liver transplant recipients. 11 The C2 ranges found in the present study must not necessarily represent ideal values, but can probably be used as guidance of CsA dosing in some patients, as a complement to trough measures for example when using concomitant drugs that may cause pharmacokinetic interactions. A previously published study on HSCT patients, comparing C2 values after continuous and 2-h infusion of 1.5 mg/kg twice daily of CsA, reported CsA concentrations between 659 and approximately 1400 ng/ml at the end of 2-h infusions.…”

“…There seems to be a consensus that in the early posttransplant period, and in patients with poor or erratic drug absorption, additional C2 sampling is valuable to support the individual dosing. 10,11 C2 monitoring of oral CsA microemulsion therapy has not been investigated previously in haematopoietic stem cell transplantation (HSCT) patients. Obtained and/or optimal C2 concentrations must not necessarily equal those achieved or targeted in solid organ transplantation.…”