Pharmacokinetics and bioavailability of mycophenolic acid after intravenous administration and oral administration of mycophenolate mofetil to heart transplant recipients

Abstract

The aim of this prospective study was to characterize the multiple-dose pharmacokinetics of mycophenolic acid (MPA) after administration of a 3-hour intravenous (IV) infusion of mycophenolate mofetil (MMF, CellCept) at a dose level of 1.5 g every 12 hours for 5 full days to cardiac allograft recipients and to compare the bioavailability of MPA after a switch from the IV infusion to an oral dose of 1.5 g every 12 hours from day 6. In addition to MMF, patients received cyclosporine and prednisolone. Blood (EDTA) samples for full pharmacokinetic profiles were obtained for 9 patients on days 3 and 5 (IV MMF) and on days 6 and 10 (oral MMF). They were centrifuged within 45 minutes of collection, and plasma was stabilized by addition of ortho-phosphoric acid to prevent in vitro conversion of MMF to MPA. Plasma concentrations of MPA were determined using a validated HPLC procedure. The median MPA AUC on day 6 (29.7 mg.h/L) after the first oral dose was slightly lower than the AUCs on the other study days (34.2, 33.8, and 33.8 mg.h/L on days 3, 5, and 10, respectively). Pairwise comparison of the individual days revealed statistically significant (P<0.05) differences between day 6 and day 3 and between day 5 and day 3. The Cmax on day 6 was significantly lower than that on study days 3 and 5. The bioavailability of MPA from the oral MMF formulation was estimated as the ratio of the AUC on day 6 or 10 to the AUC on day 5 when steady state was presumed to have been reached with the IV formulation. The mean ratios (expressed as percentage) for the log-transformed AUCs were 91.6% and 107.8% on days 6 and 10, respectively, relative to day 5. The 90% confidence interval (CI) on day 6 (79.3% to 105.8%) was marginally below the range (80%-125%) required to conclude that the formulations are bioequivalent, whereas on day 10 the 90% CI (93.3% to 124.7%) was within this range. In the case of the Cmax values, however, the 90% confidence intervals fell outside of this range (day 6, 57.2% to 92.8%; day 10, 70.6% to 114.9%). The results of this study show that heart transplant recipients receiving the IV formulation of MMF (1.5 g BID) are not subject to a greater drug exposure than that seen with the oral formulation (1.5 g BID) and that the oral MMF formulation shows excellent, high, and consistent bioavailability (mean 95%) based on comparison with the IV formulation.