Correlation of Mycophenolic Acid Pharmacokinetic Parameters with Side Effects in Kidney Transplant Patients Treated with Mycophenolate Mofetil

Abstract

Background: Mycophenolate mofetil (MMF) is widely used in organ transplantation to prevent acute rejection. Because MMF can produce hematologic and/or gastrointestinal toxicity, therapeutic monitoring is becoming mandatory. This study was designed to investigate the relationship between the clinical 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 (desired creatinine clearance, 40 mL/min), at 3 months after grafting, and at every clinical event (e.g., side effect or rejection). All patients received a 10-day course of anti-thymocyte globulin, cyclosporine, MMF (1 g twice daily), and steroids. Results: We divided the 31 patients into two groups (groups 1 and 2). Ten patients (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 trough concentrations (Cmin) were 1.63 ± 1.07 and 2.29 ± 1.16 mg/L, respectively (P = 0.06), and the areas under the curve (AUCs) for MPA from t0 to t12 h (MPA-AUC0–12h) were 39.80 ± 15.29 and 62.10 ± 21.07 mg · h/L, respectively (P = 0.0005, two-sample t-test). Three patients experienced acute graft rejection after the oral MMF dose was reduced because of side effects. In this group, the MPA-Cmin and MPA-AUC were significantly lower by the time acute rejection occurred (1.00 ± 0.45 mg/L and 25.00 ± 6.20 mg · h/L, respectively). At a fixed dose (1 g twice per day), we compared the pharmacokinetic parameters of MPA [Cmin, the MPA concentration 30 min after the oral dose of MMF (C30), and AUC] according to the presence or absence of side effects in the two groups. Cmin and AUC did not differ between the two groups [Cmin = 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 C30 was significantly higher in group 2 than in group 1 (C30 = 32.99 ± 12.59 vs 7.45 ± 5.40 mg/L; P <0.0001). Conclusions: Our results demonstrate a pharmacokinetic/pharmacodynamic relationship between MPA and clinical events. At a fixed dose of 2 g/day, a high C30 is associated with increased risk for side effects. This study suggests that dividing the MMF daily oral dose into more than two divided doses might prevent early MPA toxicity.

Higher exposure to mycophenolic acid with sirolimus than with cyclosporine cotreatment

“…15 High MPA AUCs have been associated with an increased risk of side effects, mostly leukopenia. 5 One might speculate that some of the side effects observed in patients treated with sirolimus, particularly in the immediate posttransplant period, such as leukopenia, 16 might be partly related to an overdosing of MPA.…”

Enteric‐coated mycophenolate sodium delivers bioequivalent MPA exposure compared with mycophenolate mofetil

“…For each patient, 2.6 mL of blood was withdrawn from a forearm vein into a heparin tube before drug administration and at 15 time points up to 48 h after dosing. The time points chosen were 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3,4,8,12,16,24,36, and 48 h post-dose. MPA and MPAG concentrations in plasma were determined by HPLC (sensitivity limit, 0.1 lg/mL) (data on file, Novartis Pharma AG).…”

Pharmacokinetic and pharmacodynamic analysis of enteric‐coated mycophenolate sodium: limited sampling strategies and clinical outcome in renal transplant patients

“…Reduction of the standard dose results in fewer sideeffects, although increases the risk of acute rejection. It has been shown that the area under the concentration-time curves (AUCs) vary widely in patients following the same MPA dosage [5].Therapeutic drug monitoring (TDM) might be useful for optimizing individual immunosuppressive therapy and improving allograft function [6][7][8][9][10]. In the French APOMYGRE study, titration of MMF dose according to plasma MPA concentrations resulted in an increased MPA exposure and a reduced incidence of acute rejection episodes without an increased risk of infections or haematological disorders [11].…”