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.

Pharmacokinetics of Mycophenolate Mofetil and Development of Limited Sampling Strategy in Early Kidney Transplant Recipients

“…Mycophenolic acid is primarily metabolized to the inactive metabolite 7- O -MPA glucuronide, which undergoes EHR ( Armstrong et al, 2005 ). Due to EHR a second peak was identified in 6–12 h following MMF oral administration ( Bullingham et al, 1998 ).…”

Middle East Respiratory Syndrome and Severe Acute Respiratory Syndrome: Current Therapeutic Options and Potential Targets for Novel Therapies

“…Although MPA has weak inhibitory activity against SARS-CoV in vitro, it has promising activity against MERS-CoV [ 80 , 112 ]. A potential alternative to MPA, the prodrug mycophenolate mofetil, has improved oral bioavailability [ 120 ]. Mycophenolate mofetil evaluated in the common marmoset model of MERS did not reduce disease manifestations compared to that observed in control subjects [ 121 ].…”

The Evolution of Population Pharmacokinetic Models to Describe the Enterohepatic Recycling of Mycophenolic Acid in Solid Organ Transplantation and Autoimmune Disease

“…This can be observed in the MPA concentration-time profiles that show varying lag times, varying times to maximal MPA concentration and double peaks in the absorption and post-absorption phases. [14,15] The large BSV and BOV in MPA pharmacokinetics [16] has been attributed to differences in albumin concentrations, change of renal and hepatic function, bilirubin and haemoglobin concentrations, bodyweight, sex, concomitant medication [13] and race. In addition, the exposure to and disposition of MPA are influenced by multiple enzymes and various transporters in which several functional single nucleotide polymorphisms (SNPs) have been found.…”