Patient management by Neoral C2 monitoring: An international consensus statement1

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Abstract
The Consensus on Neoral C2: Expert Review in Transplantation (CONCERT) attendees achieved consensus on the following points, based on currently available data from independent clinical studies using Neoral (cyclosporine microemulsion): 1. Scientific validation of Neoral C2 monitoring 1.1 An understanding of cyclosporine pharmacokinetics is critical for designing a monitoring strategy that maximizes clinical outcome following organ transplantation 1.2 Neoral absorption during the first 4 hours postdose (AUC0–4) represents the period of greatest variability among patients. Adequate CsA absorption during this period is important for effective rejection prophylaxis in the early posttransplant phase 1.3 C0 does not correlate well with AUC0–4 in patients receiving Neoral 1.4 C2 is the best single time-point predictor of AUC0–4 in all types of Neoral-treated transplant patient populations that have been studied (adult renal, liver, heart and lung patients, and pediatric renal and liver transplant recipients) 1.5 Additional CsA concentration sampling beyond the C2 time point, such as C6, may be required in low absorbers of CsA 2. Clinical data in de novo adult renal transplant patients 2.1 C0 monitoring in patients receiving Neoral distinguishes poorly between those who will experience acute rejection and those who will remain rejection-free 2.2 Existing data indicate that higher C2 levels are highly correlated with a lower risk of acute rejection during the early posttransplant period in patients receiving Neoral. Data on outcomes beyond 1 year are awaited 2.3 The association between C2 and risk of acute rejection is maintained in Neoral-treated patients who receive an antibody induction agent or concomitant mycophenolate mofetil (MMF) therapy 2.4 Achieving an adequate C2 level early after transplantation is associated with reduced risk of acute rejection in adult renal transplant recipients 2.5 Adjustment of Neoral dose based on C2 monitoring does not appear to result in impaired early renal function in the short-term, if slow absorbers are identified and managed appropriately. Long-term data are pending 3. Clinical data in de novo adult liver transplant patients 3.1 Patient management with Neoral C2 monitoring reduces the incidence and severity of acute rejection compared to C0 monitoring 3.2 Renal function is not compromised by C2 monitoring in adult liver transplant patients receiving Neoral 4. Clinical outcomes in maintenance renal and liver transplant patients 4.1 Patient management with Neoral C2 monitoring can improve renal function in maintenance patients by identifying patients who are receiving excessive CsA 4.2 Using C2 monitoring in maintenance patients can also reduce the incidence and severity of hypertension by identifying patients who are receiving excessive CsA 4.3 Current data suggest that there is an association between C2 level and risk of chronic allograft nephropathy, in adult renal transplant patients receiving Neoral 5. C2 targets for adult renal transplant patients 5.1 Guideline C2 targets have been proposed for the first month posttransplant in adult renal transplant patients receiving Neoral, with subsequent step-wise reductions in C2 target over time 5.2 Long-term target C2 levels for prevention of chronic allograft nephropathy remain to be confirmed 6. C2 targets for adult liver transplant patients 6.1 Guideline C2 targets have been proposed for adult liver transplant recipients receiving Neoral 7. C2 targets for other transplant patient types 7.1 C2 target levels have not yet been established for cardiothoracic organ recipients, living-related liver transplant recipients, kidney-pancreas transplant patients, or pediatric transplant patients receiving Neoral 8. Accuracy of C2 sampling 8.1 There is a 15-minute “window of opportunity” before and after the 2-hour time point during which the C2 sample can be taken in order to remain within a 10% margin of error 8.2 In most instances, C2 targets do not require adjustment for different immunoassay types currently available 9. Pharmacoeconomics 9.1 Neoral C2 monitoring is at least cost neutral compared to C0 monitoring and may generate cost savings in adult renal transplant patients 10. Conclusions of the CONCERT conference 10.1 C2 monitoring is the optimal method to monitor Neoral in adult de novo renal and liver transplant patients (2) 10.2 Preliminary data indicate that Neoral C2 monitoring may have clinical benefits in maintenance adult renal and liver transplant recipients who are receiving excessive CsA and in whom the Neoral dose is reduced 10.3 Maintenance patients who are experiencing suspected CsA-related toxicity may benefit from use of Neoral C2 monitoring to detect CsA overexposure 10.4 Further data sre required from prospective, randomized multicenter trials to evaluate the possible long-term clinical benefits of adopting Neoral C2 monitoring in de novo and maintenance transplant patients, both in terms of rejection prophylaxis and overall safety profile