Combination therapy with tacrolimus and mycophenolate mofetil following cardiac transplantation: Importance of mycophenolic acid therapeutic drug monitoring

Background: Interest has recently been expressed in tacrolimus and mycophen olate mofetil (MMF), two potent immunosuppressants, for a variety of transp lant indications. The efficacy of this combination was assessed as primary therapy following cardiac transplantation. Methods: Forty-five patients were enrolled; 15 into Phase I and 30 to Phase II of the study. Intravenous tacrolimus was administered for 2-3 days to a ll patients prior to conversion to oral therapy; target blood concentration s were 10-15 ng/mL. Treatment also consisted of steroids and MMF. During Ph ase I, a fixed 2 g/day dose of MMF was given whilst doses were adjusted acc ording to mycophenolic acid (MPA) plasma levels during Phase II (target ran ge 2.5-4.5 mu g/mL). Mean follow-up was 696 +/- 62 days and 436 +/- 88 days for Phases I and II, respectively. Results: Phase I: Patient survival was 100%. Rejection was diagnosed in 66. 7% of patients (mean number of episodes per patient 1.33 +/- 1.18). Retrosp ective analyses indicated that whereas mean MPA plasma levels >3.0 mu g/mL were not associated with rejection, no correlation was found with tacrolimu s blood concentrations. Phase II: A survival rate of 96.7% was evident, one patient having died from aspergillosis. Diagnoses of rejection were made i n 10.0% of patients (0.10 +/- 0.31 episodes per patient) and confounding fa ctors were present in all 3 cases. MPA trough levels were 1.0 +/- 0.3 mu g/ mL at this time. Resolution was apparent following pulse steroid therapy. S teroids were successfully withdrawn from all patients who completed 6 month s' treatment. Conclusions: Combination therapy with tacrolimus and MMF is associated with suppression of acute myocardial rejection; however, this is dependent upon routine therapeutic drug monitoring.