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 s trategies of MMF are not routinely adjusted based on mycophenolic acid (MPA ) area under the concentration-time curve (AUC), MPA trough, or free MPA (f MPA) AUC values. Methods: To determine the clinical significance of MPA concentrations follo wing orthotopic heart transplantation (OHT), we measured pre-dose MPA troug h, MPA free fraction, an estimated MPA AUC using an abbreviated sampling sc hedule, and fMPA AUC in 38 consecutive patients. We measured MPA concentrat ions using a validated high-performance liquid chromatography method and gr aded endomyocardial biopsies based on the International Society for Heart a nd 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 pa tients with Grade 0 (n = 22), Grade 1 (n = 13), or Grade 2/3 (n = 3). The M PA AUC values were lower in patients with Grade 2/3 than in patients with G rade 0 (26.1 +/- 6.6 vs 42.8 +/- 14.0 mug/ hour/ml, p < 0.08) or Grade 1 re jection (26.1 +/- 6.6 vs 51.7 +/- 17.5 <mu>g/hour/ml, p < 0.05). The fMPA A UC values were lower in patients with Grade 2/3 than with patients with Gra de 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 A UC values are associated with cardiac allograft rejection in heart transpla nt recipients. Individualizing MMF dosing based on MPA determinations may m inimize the risk of rejection following OHT.