A retrospective analysis of mycophenolic acid and cyclosporin concentrations with acute rejection in renal transplant recipients

Abstract

Objectives: Although monitoring of cyclosporin (CsA) is standard clinical practice postrenal transplantation, mycophenolic acid (MPA) concentrations are not routinely measured. There is evidence that a relationship exists between MPA area under the concentration-time curve (AUC) and rejection. In this study, a retrospective analysis was undertaken of 27 adult renal transplant recipients.

Methods: Patients received CsA and MPA therapy and had a four-point MPA AUC investigation. The relationship between MPA AUC performed in the first week after transplantation, as well as median trough cyclosporin concentrations, and clinical outcomes in the first month posttransplant were evaluated.

Results: A total of 12 patients experienced biopsy proven rejection (44.4%) and 4 patients had gastrointestinal adverse events (14.8%). A statistically significant relationship was observed between the incidence of biopsy proven rejection and both MPA AUC (p = 0.02) and median trough CsA concentration (p = 0.008). No relationship between trough MPA concentration and rejection was observed (p = 0.21). Only 3 of 11 (27%) patients with an MPA AUC > 30 mg.h/L and a median trough CsA > 175 μg/L experienced acute rejection, compared with a 56% incidence of rejection for the remaining 16 patients. Patients who experienced adverse gastrointestinal events had significantly lower MPA AUC (p = 0.04), but median trough CsA concentrations were not significantly different (p = 0.24). Further, 3 of these 4 patients had rejection episodes.

Conclusions: In addition to standard CsA monitoring, we propose further investigation of the use of a 4-point sampling strategy to predict MPA AUC in the first week posttransplant, which may facilitate optimization of mycophenolate mofetil dose at a time when patients are most vulnerable to acute rejection.

Introduction

Mycophenolate mofetil (MMF), the ester prodrug of mycophenolic acid (MPA), has been shown to reduce the incidence of acute rejection up to 6 months following allogenic renal transplantation [1], [2]. MMF is administered as a fixed dose of 2 g per day and monitoring of MPA is not routinely performed. Clinical experience has demonstrated a relationship between cyclosporin (CsA) blood concentrations and outcome after kidney transplantation [3].

Large inter-patient variability in the MPA pharmacokinetics of individuals receiving the same dose of MMF has been observed [4], [5], [6]. Several studies have shown a relationship between MPA area under the concentration-time curve (AUC) and biopsy proven rejection [7], [8], [9]. These data suggest a case for routine monitoring of MPA.

The measurement of MPA AUC requires multiple blood samples over the dosing interval and is both clinically impractical and expensive. It has been proposed that limited sampling strategies may provide a suitable measure for MPA AUC [6], [9], [10], [11]. We have previously reported that a 4-point model provides superior AUC predictability than other published strategies [12].

The aim of this study was to assess the relationship between a single four-point MPA AUC measurement performed in the first week after transplant, as well as median trough cyclosporin concentration before rejection or during the first month, and clinical outcomes in the first month following renal transplantation.