| Abstract: | ![]()
Background and objectives: Adequate early mycophenolic acid (MPA) exposure is associated with lower rates of acute rejection in renal transplantation. The aim of this randomized controlled trial was to determine if higher initial mycophenolate mofetil (MMF) doses increased the proportion of patients reaching therapeutic MPA levels (30 to 60 mg·h/L) by day 5.Design, setting, participants, & measurements: De novo renal transplant patients were randomized to receive intensified dosing of MMF (1.5 g twice daily on days 1 to 5, then 1.0 g twice daily) or standard dosing (1.0 g twice daily). All recipients received tacrolimus and prednisone. Full MPA areas under the curve (AUCs) were completed on days 3 and 5, whereas a limited sampling strategy was utilized at four subsequent time points.Results: At day 5, 47.5% of the MMF 3-g arm achieved the MPA therapeutic window versus 54.4% of the MMF 2-g arm. However, MPA AUC levels were significantly higher in the 3-g arm at day 3 and 5. This resulted in a trend for fewer treated acute rejections at 6 months. Significantly more acute rejections (treated, biopsy-proven including and excluding borderline) occurred in patients with MPA AUC levels <30 mg·h/L compared with those ≥30 mg·h/L at day 5. No significant differences were seen in common adverse events.Conclusions: A limited intensified dose of MMF increased early MPA exposure and was well tolerated. Further studies are required to determine whether limited intensified MMF dosing can reduce acute rejection.Mycophenolate mofetil (MMF, CellCept®) is an effective immunosuppressant and a key component of the immunosuppression regimen in most renal allograft recipients (1,2). A recent review and preliminary meta-analysis showed that overall graft survival is better with MMF compared with azathioprine when administered with calcineurin inhibitors (3,4). Traditionally, MMF is administered as a fixed dose without therapeutic drug monitoring (TDM). It remains unclear what role TDM of MMF has in improving graft and patient outcomes.There is a growing body of evidence supporting the utility of TDM. The drug has a large interpatient variability, with a 6-fold variation for a fixed daily dose (5). Van Gelder and his colleagues demonstrated a clear dose-effect relationship between acute rejection and 12-hour mycophenolic acid (MPA) area under the curve (AUC) exposures (6). MPA AUC values between 30 and 60 mg·h/L are proposed to be the target therapeutic window for patients treated with cyclosporine and prednisone (5). However, nearly 50% of cyclosporine-treated subjects are below the therapeutic target within the first week when administered the standard MMF dose of 2 g daily posttransplantation (7). More recently, a randomized controlled trial demonstrated that a concentration-controlled arm (dosed to achieve a mean exposure of 45 mg·h/L) resulted in significantly less rejection as compared with a standard-dosed arm (8).However, TDM is problematic given the poor correlation with any convenient single point concentration and AUC (5). Furthermore, there is some evidence that early exposure is important, with day-3 values being better predictors of acute rejection as compared with later values (7,9). Accordingly, clinicians would need to monitor exposure early and aim to intensify treatment within the first 3 days. Nonsteady-state conditions and the requirement for rapid turnaround times make TDM problematic in the early posttransplantation period. Alternatively, higher initial doses could either be given during the early critical period or until TDM can be performed. However, the safety profile of this approach is unknown. In addition, tacrolimus is now the most commonly used calcineurin inhibitor in the United States and there is limited information on MMF exposure when used in combination with tacrolimus (2,10).This study compared the ability of early, intensified, but limited-duration MMF dosing to increase the number of patients adequately exposed to MPA within the first week posttransplantation as compared with standard dosing in renal transplant recipients treated with tacrolimus. |
