title: 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 (C(min)) 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 t(0) to t(12 h) (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 experienced 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 +/- 6.20 mg. h/L, respectively). At a fixed dose (1 g twice per day), we compared the pharmacokinetic parameters of MPA [C(min), the MPA concentration 30 min after the oral dose of MMF (C(30)), and AUC] according to the presence or absence of side effects in the two groups. C:(min) and AUC did not differ between 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 relationship between MPA and clinical events. At a fixed dose of 2 g/day, a high C(30) 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.
authors.affiliation: Department of Kidney and Pancreas Transplantation, University Hospital Saint Luc, Université Catholique de Louvain, Avenue hippocrate, 10, 1200 Brussels, Belgium. Michel.Mourad@chir.ucl.ac.be
authors.forename: M
authors.initials: M
authors.lastname: Mourad
authors.forename: J
authors.initials: J
authors.lastname: Malaise
authors.forename: D
authors.initials: D
authors.lastname: Chaib Eddour
authors.forename: M
authors.initials: M
authors.lastname: De Meyer
authors.forename: J
authors.initials: J
authors.lastname: König
authors.forename: R
authors.initials: R
authors.lastname: Schepers
authors.forename: J P
authors.initials: JP
authors.lastname: Squifflet
authors.forename: P
authors.initials: P
authors.lastname: Wallemacq
mesh_terms: D000293:Adolescent; D000328:Adult; D000961:Antilymphocyte Serum / Q000627:therapeutic use; D016572:Cyclosporine / Q000627:therapeutic use; D004359:Drug Therapy, Combination; D005260:Female; D006084:Graft Rejection; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000009:adverse effects* / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D011355:Prodrugs / Q000009:adverse effects* / Q000493:pharmacokinetics* / Q000627:therapeutic use
chemical_list: D000961:Antilymphocyte Serum; D007166:Immunosuppressive Agents; D011355:Prodrugs; D016572:Cyclosporine; D009173:Mycophenolic Acid