Mycophenolate pharmacokinetics in early period following lung or heart transplantation

BACKGROUND: The available pharmacokinetic and pharmacodynamic data on mycophenolic acid (MPA), the pharmacologically active metabolite of mycophenolate mofetil (MMF), are derived largely from renal transplant patients, not thoracic transplant recipients. OBJECTIVE: To evaluate, in a pilot study, the pharmacokinetics of MPA at 3 different times in the early period (up to the first 9 mo) following lung or heart transplantation. METHODS: Nine patients were entered into this open-label study. Upon administration of a steady-state morning MMF dose, blood samples were collected at 0, 20, 40, 60, and 90 minutes and at 2, 4, 6, 8, 10, and 12 hours after the dose at 3 times (denoted as sampling periods 1, 2, and 3) in the early posttransplant period. Total MPA concentrations were measured by a validated HPLC method with ultraviolet detection and followed by ultrafiltration of pooled samples for unbound MPA concentrations. Pharmacokinetic parameters (maximal concentration [C-max], dose-normalized C-max, time to C-max, minimum concentration, predose concentration, AUC, dose-normalized AUC, free fraction, free AUC) were calculated by traditional noncompartmental methods. RESULTS: Patient characteristics included 7 men and 2 women, 5 lung and 4 heart transplant recipients, mean +/- SD age 53 +/- 11 years, and weight 77 +/- 14 kg. All patients were receiving prednisone and cyclosporine (with the exception of 2 pts. on tacrolimus during sampling periods 2 and 3). Sampling periods 1, 2, and 3 occurred on posttransplant days 15 13, 56 33, and 125 73, respectively. No significant differences were found between sampling periods in any pharmacokinetic parameter. Drug exposure as evaluated by AUC was 39.95 +/- 44.86, 25.24 +/- 25.68, and 43.96 +/- 38.67 mug.h/mL during sampling periods 1, 2, and 3, respectively, (p > 0.05). CONCLUSIONS: As of September 26, 2003, this is the first study to systematically evaluate MPA pharmacokinetics in thoracic transplant recipients at 3 different time points during the early posttransplant period. Wide interpatient variability in MPA pharmacokinetics was observed, thus emphasizing the need to individualize dosing of MMF and to further evaluate important pharmacokinetic/pharmacodynamic parameters and endpoints that impact on clinical outcomes. Further studies involving more patients and pharmacodynamic outcomes are underway to help identify optimal MMF strategies.