title: Mycophenolic acid concentrations are associated with cardiac allograft rejection.
abstract: BACKGROUND
  Mycophenolate mofetil (MMF) therapy decreases the incidence of allograft rejection following solid-organ transplantation. Current dosing strategies of MMF are not routinely adjusted based on mycophenolic acid (MPA) area under the concentration-time curve (AUC), MPA trough, or free MPA (fMPA) AUC values.
  
  
  METHODS
  To determine the clinical significance of MPA concentrations following orthotopic heart transplantation (OHT), we measured pre-dose MPA trough, MPA free fraction, an estimated MPA AUC using an abbreviated sampling schedule, and fMPA AUC in 38 consecutive patients. We measured MPA concentrations using a validated high-performance liquid chromatography method and graded endomyocardial biopsies based on the International Society for Heart and Lung Transplantation (ISHLT) grading system.
  
  
  RESULTS
  The MPA values for the study group were as follows: MPA trough of 1.2 +/- 0.6 microg/ml; MPA free fraction of 1.9 +/- 0.4%; MPA AUC of 44.5 +/- 16. 1 microg/hour/ml; and fMPA AUC of 0.83 +/- 0.30 microg/hour/ml. We compared patients with Grade 0 (n = 22), Grade 1 (n = 13), or Grade 2/3 (n = 3). The MPA AUC values were lower in patients with Grade 2/3 than in patients with Grade 0 (26.1 +/- 6.6 vs 42.8 +/- 14.0 microg/hour/ml, p < 0.08) or Grade 1 rejection (26.1 +/- 6.6 vs 51.7 +/- 17.5 microg/hour/ml, p < 0.05). The fMPA AUC values were lower in patients with Grade 2/3 than with patients with Grade 0 (0.49 +/- 0.11 vs 0.81 +/- 0.25 microg/hour/ml, p < 0.05) or Grade 1 (0.49 +/- 0.25 vs 0.95 +/- 0.34 microg/hour/ml, p < 0.05) rejection. We noted a trend in MPA trough concentrations between patients with Grade 2/3 vs 0 (0.65 +/- 0.15 vs 1.20 +/- 0.58 microg/ml, p = 0.15) and Grade 1 (0.65 +/- 0.15 vs 1.24 +/- 0.72 microg/ml, p = 0.14) rejection.
  
  
  CONCLUSIONS
  These preliminary results suggest that lower MPA AUC and fMPA AUC values are associated with cardiac allograft rejection in heart transplant recipients. Individualizing MMF dosing based on MPA determinations may minimize the risk of rejection following OHT.
authors.affiliation: Department of Medicine, New England Medical Center, Boston, Massachusetts 02111, USA. ddenofrio@lifespan.org
authors.forename: D
authors.initials: D
authors.lastname: DeNofrio
authors.forename: E
authors.initials: E
authors.lastname: Loh
authors.forename: A
authors.initials: A
authors.lastname: Kao
authors.forename: M
authors.initials: M
authors.lastname: Korecka
authors.forename: F W
authors.initials: FW
authors.lastname: Pickering
authors.forename: K A
authors.initials: KA
authors.lastname: Craig
authors.forename: L M
authors.initials: LM
authors.lastname: Shaw
mesh_terms: D000328:Adult; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D005260:Female; D005500:Follow-Up Studies; D006084:Graft Rejection / Q000188:drug therapy* / Q000276:immunology; D016027:Heart Transplantation / Q000276:immunology*; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*
chemical_list: D007166:Immunosuppressive Agents; D009173:Mycophenolic Acid