Equivalent Pharmacokinetics of Mycophenolate Mofetil
African-American (AA) renal transplant recipients require higher doses of mycophenolate mofetil (MMF) than Caucasians. A hypothesized pharmacokinetic (PK) difference was tested in stable renal transplant recipients. Whole blood was collected before, and 20, 40 and 75 min, and 2, 3, 4, 6, 8 and 12 h after the MMF dose. Mycophenolic acid (MPA) and its glucuronide metabolite (MPAG) were analyzed using HPLC. Analysis of variance was performed for the primary end-points of dose-adjusted PK parameters AUC_0-12 and C_max of MPA using log-transformed values. Differences between races and genders were estimated: 90% confidence intervals (CI) were calculated. Back-transformation gave estimates of the race and gender ratio and their CI. Equivalence of the groups was determined if the 90% confidence limits were included in the interval (0.80, 1.25). The calculated PK parameters were comparable among the four subgroups (Caucasian, AA, Male, Female). The 90% CIs for the ratio of dose-adjusted AUC_0-12 of MPA between races were between 89.7 and 112.9%. There were no race, gender or race-by-gender effects (p-values = 0.196) nor differences between diabetics and nondiabetics. This study demonstrates that dosing requirement for MMF in AA and Caucasians is unlikely to be related to different exposures to MPA.

Mycophenolate mofetil (MMF, CellCept, Roche Pharmaceuticals, Basel, Switzerland) is an approved drug currently used in conjunction with other immunosuppressive agents for the prevention of acute rejection. Mycophenolate mofetil, the 2-morpholinoethyl ester of mycophenolic acid (MPA), is rapidly and extensively absorbed following oral administration and hydrolyzed to form MPA, which is the active immunosuppressive metabolite. Mycophenolic acid is a potent and specific inhibitor of de novo purine synthesis and blocks the proliferation of both T and B lymphocytes. Mycophenolic acid is further metabolized to form a glucuronide conjugate (MPAG) that is pharmacologically inactive.

In a post hoc analysis of the pivotal MMF trial, it was noted that African-American (AA) recipients randomized to MMF only demonstrated a statistically significant efficacy advantage over recipients randomized to azathioprine if they received a higher dose (1.5 g b.i.d.) of MMF. The explanation for this is not clear and could include pharmacokinetic differences of MMF in AA vs. Caucasian recipients. Although a major difference in the pharmacokinetics of MMF between AA and Caucasian renal transplant recipients was not detected in previous clinical trials conducted with MMF, the possible existence of minor differences, which translates into the observed clinical result, could not be totally excluded. In addition, a previous study in rheumatoid arthritis (RA) patients suggested that the systemic exposure to MPA might be lower in AAs than in Caucasians, but these results were inconclusive owing to the small study sample size and confounding factors such as difference in body weight and smoking habits; factors that are both thought to affect MMF pharmacokinetics (PKs).

The current study was designed to rigorously compare the steady-state pharmacokinetics of twice daily oral MMF in male and female AA and Caucasian stable renal transplant patients in order to test the hypothesis that the clinical result would be a direct effect of pharmacokinetic differences.