Current target ranges of mycophenolic acid exposure and drug-related adverse events: A 5-year, open-label, prospective, clinical follow-up study in renal allograft recipients

Abstract

Background: Two recent randomized clinical trials—Fixed Dose Versus Concentration Controlled and the Apomygre—evaluating the benefit of therapeutic drug monitoring of mycophenolate mofetil (MMF) in renal allograft recipients reported conflicting results. In both studies, target mycophenolic acid (MPA) AUC 0-14;12h ranges (ie, values used to guide MMF dosing) were derived from a previous study establishing target MPA AUC 0-12h ranges in cyclosporine-treated patients between 30 and 60 mg/L . h -1. Both studies found an association between MPA exposure and acute rejection. However, only one of the studies found concentrationcontrolled MMF dosing to be significantly associated with less biopsy-proven acute-rejection episodes compared with fixed dosing. No reduced incidence of MMF-related adverse events (AEs) was observed in either of the 2 trials when MMF concentration-controlled and fixed dosing were compared. Objective: The aim of this study was to assess the clinical utility of target MPA AUC 0-12h ranges between 30 and 60 mg/L . h -1 in associating drug exposure with AEs within different time windows after transplantation, thereby identifying patients at increased risk for MMF-related AEs. The effects of single nucleotide polymorphisms (SNPs) of the uridine glucuronosyltransferase 1A9 (UGT1A9) and MRP2 genes (ie, coding for the UGT1A9 and the multidrug resistance protein transporter MRP2)—both involved in MPA metabolism—on stratified MPA exposure were assessed by applying the current advised target MPA AUC 0-12h ranges. Methods: We conducted a 5-year clinical follow-up study in renal allograft recipients in whom MPA exposure was measured at 7 days, 6 weeks, 3 months, 1, 3, and 5 years post transplantation using abbreviated AUC measurements. MMF dose adjustments were based on clinical indications (eg, persistent leukopenia, chronic afebrile diarrhea, BK-polyomavirus infection of the renal allograft). Clinicians were blinded to the results of the AUC measurements. Results: One hundred white de novo renal allograft recipients (59 men, 41 women; mean [SD] age 51.4 [13.8] years) were included in this study. Ninety-eight patients received a renal allograft from a deceased donor. Significantly more episodes of leukopenia were associated with MPA AUC 0-12h ranges >60 mg/L . h -1 (P = 0.03). Anemia was also significantly associated with higher MPA exposure ranges (incidence of anemia was 40.8%, 52.2%, and 64.3% for MPA AUC 0-12h ranges <30, 30-60, and >60 mg/L . h -1, respectively; P = 0.004). Mean MPA AUC 0-12h was significantly higher in the time window immediately preceding or following leukopenia (mean [SD] 59.7 [31.0] vs 46.5 [26.0] mg/L . h -1; P = 0.004) and anemia (mean [SD] hemoglobin <12 g/L . d -1: 52.5 [30.0] vs 42.2 [21.2] mg/L . h -1, P = 0.002; hemoglobin <10 g/L . d -1: 56.2 [32.5] vs 45.6 [24.7] mg/L . h -1, P = 0.005). No association was found between incident episodes