Mycophenolic acid concentrations are associated with cardiac allograft rejection

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 mug/ml; MPA free fraction of 1.9 +/- 0.4%; MPA AUC of 44.5 +/- 16.1 mug/hour/ml; and fMPA AUC of 0.83 +/- 0.30 mug/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 mug/ hour/ml, p < 0.08) or Grade 1 rejection (26.1 +/- 6.6 vs 51.7 +/- 17.5 <mu>g/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 <mu>g/hour/ml, p < 0.05) or Grade 1 (0.49 +/- 0.25 vs 0.95 +/- 0.34 <mu>g/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 <mu>g/ml, p = 0.15) and Grade 1 (0.65 +/- 0.15 vs 1.24 +/- 0.72 mug/ml, p = 0.14) rejection. Conclusion: 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.