Correlation of mycophenolic acid pharmacokinetic parameters with side effects in kidney transplant patients treated with mycophenolate mofetil

Background: Mycophenolate mofetil (MMF) is widely used in organ transplanta tion to prevent acute rejection. Because MMF can produce hematologic and/or gastro-intestinal toxicity, therapeutic monitoring is becoming mandatory. This study was designed to investigate the relationship between the clinica l events and the pharmacokinetics of mycophenolic acid (MPA) in adult renal transplantation, Methods: Thirty-one adult kidney recipients were prospectively included in the study. MPA pharmacokinetic profiles (blood sampling at 0, 0.5, 1, 2, 4, 6, and 12 h after MMF oral dose) were obtained after transplantation (desi red creatinine clearance, 40 mL/min), at 3 months after grafting, and at ev ery clinical event (e.g., side effect or rejection). All patients received a 10-day course of anti-thymocyte globulin cyclosporine, MMF (Ig twice dail y), and Steroids. Results: We divided the 31 patients into two groups (groups 1 and 2). Ten p atients (32%; group 1) had uneventful outcomes, and 21 patients (68%; group 2) presented with MPA-related side effects. For groups 1 and 2, the MPA tr ough concentrations (C-min) were 1.63 +/- 1.07 and 2.29 +/- 1.16 mg/L, resp ectively (P = 0.06), and the areas under the curve (AUCs) for MPA from t(0) , to t(12h) (MPA-AUC(0-12h)) were 39.80 +/- 15.29 and 62.10 +/- 21.07 mg .h /L, respectively (P = 0.0005, two-sample t-test). Three patients experience d acute graft rejection after the oral MMF dose was reduced because of side effects. In this group, the MPA-C-min and MPA-AUC were significantly lower by the time acute rejection occurred (1.00 +/- 0.45 mg/L and 25.00 +/- 6.2 0 mg .h/L respectively). At a fixed dose (1 g twice per day), we compared t he pharmacokinetic parameters of MPA [C-min, the MPA concentration 30 min a fter the oral dose of MMF (C-30)(,) and AUC] according to the presence or a bsence of side effects in the two groups. C-min and AUC did not differ betw een the two groups [C-min = 2.22 +/- 1.13 vs 2.17 +/- 1.13 mg/L (P = 0.9); AUC = 66.82 +/- 29.87 vs 55.70 +/- 11.74 mg .h/L (P = 0.11)]; and C-30 was significantly higher in group 2 than in group 1 (C-30 32.99 +/- 12.59 vs 7. 45 +/- 5.40 mg/L; P <0.0001). Conclusions: Our results demonstrate a pharmacokinetic/pharmacodynamic rela tionship between MPA and clinical events. At a fixed dose of 2 g/day, a hig h C,, is associated with increased risk for side effects. This study sugges ts that dividing the MMF daily oral dose into more than two divided doses m ight prevent early MPA toxicity. (C) 2001 American Association for Clinical Chemistry.