Optimization of cyclosporine therapy with new therapeutic drug monitoring strategies: report from the international neoral® tdm advisory consensus meeting (vancouver, november 1997)

Abstract

CYCLOSPORINE (CsA) has a very narrow therapeutic range because of the fine line between adequate immunosuppression and the risk of drug-induced side effects. Therapeutic drug monitoring (TDM) of CsA is an essential component of the patient’s long-term management plan and involves the use of blood concentrations of the drug to individualize dosing regimens based on pharmacokinetic principles. The traditional method of optimizing a CsA dose regimen in a patient is by titrating the predose blood concentration of CsA (“trough” level) to a designated range that is considered therapeutic and nontoxic. The designated range of CsA blood concentrations has evolved from previous TDM consensus discussions that have contributed to a standardized CsA monitoring strategy that has been adopted by the majority of transplantation programs. Although CsA trough-level monitoring has developed as the standard of practice for patient management, more accurate pharmacokinetic predictors of clinical outcomes for patients receiving CsA have been identified. The area under the time-blood CsA concentration curve (AUC) was found to be the most sensitive predictor of outcomes such as acute rejection episodes and graft loss at 1 year posttransplant in adult renal transplant recipients in two independent studies. A subsequent re-evaluation of the CsA pharmacokinetic database from University of Texas identified intrapatient variability in AUCs as a significant risk factor in development of chronic rejection. There has been little movement toward the adoption of full AUC monitoring because of the impracticality, cost of multiple samples for analysis, and possibly by a resistance in the transplant community to change their standards of practice without clear evidence of benefit. The introduction of Neoralt as a superior formulation of CsA has provided us with the stimulus to reevaluate the traditional approach to therapeutic monitoring of the drug. The improved and more consistent AUCs from the Neoralt formulation compared with Sandimmunet have been demonstrated in several studies in stable and de novo renal transplant patients. Superior CsA pharmacokinetics with the Neoralt formulation compared to Sandimmunet have also been documented in liver, lung, and cardiac transplant patients. Several studies have documented a significant reduction in the incidence of acute rejection rates in Neoralt-treated versus Sandimmunet-treated de novo renal and liver transplant recipients which confirms the important influence of consistent and enhanced bioavailability of CsA on clinical outcomes in the transplant recipient. The focus on CsA pharmacokinetics and clinical outcomes has resulted in a much more extensive pharmacokinetic database from Neoralt clinical trials than all the Sandimmunet data combined over the past 15 years. This wealth of pharmacokinetic data on Neoralt has re-awakened interest in the utility of monitoring blood concentrations of cyclosporine, and subsequently has stimulated exploration of other therapeutic monitoring strategies. Examples of TDM strategies for Neoralt are listed in Table 1. The goals of this meeting were to discuss, explore, and re-evaluate therapeutic monitoring standards for Neoralt with a focus on sparse-sampling-derived AUCs and singlepoint sampling methods and to provide the transplant community with suggestions concerning first steps on a pathway toward optimizing clinical outcomes with Neoralt.