Mycophenolic acid (MPA)is the active component of mycophenolate mofetil (MMF). Low MPA exposure is associated with a higher incidence of acute GVHD and possibly worse engraftment. Therapeutic plasma targets have been proposed in hematopoietic cell transplantation (HCT), however, are difficult to achieve in adult patients with MMF doses of 2 g/day. Mycophenolate pharmaco-kinetics was prospectively studied in adults undergoing nonmyeloablative HCT who received MMF 3 g/day with CYA. The first 15 individuals received 1.5 g every 12 h and the second 15 received 1 g every 8 h. Sampling was performed in each patient with i.v. and oral administration. There were no differences in total or unbound MPA 24-h cumulative area under the curves (AUCs), concentrations at steady state (Css)or troughs between the two dosing regimens (all P>0.01). The previously proposed total MPA Css target of 3 μg/ml and trough ≥1 μ/ml were achieved in only 13–27% and 20–53% of patients, respectively, on 3 g/day. However, the 3 g/day regimens readily achieved satisfactory unbound 24-h cumulative AUC targets of 0.600 μg*h/ml in 87–100% of subjects. There appears to be no significant difference in daily MPA exposure when MMF of 3 g/day is divided into two or three equal doses.

Mycophenolate mofetil (MMF) is frequently used as part of the immunosuppressive regimen after allogeneic nonmyeloablative HCT. We and others have previously shown that low mycophenolic acid (MPA) exposure, the active component of MMF, is associated with poorer rates of engraftment and increased risk of graft-vs-host disease (GVHD). As therapeutic plasma targets are difficult to achieve in adult HCT recipients with doses of MMF 2 gm/day, higher doses are required. To determine if higher MMF doses of 3 gm/day would achieve the therapeutic plasma targets we conducted a prospective pharmacokinetic study in adult recipients of nonmyeloablative HCT treated with cyclophosphamide 50 mg/kg, fludarabine 200 mg/m2 and total body irradiation 200 cGy in combination with cyclosporine and MMF as either 1.5 gm every 12 hours (n=15) or 1 gm every 8 hours (n=15). MMF was initiated on day -3 intravenously and switched to the oral form within the first week at the same dose. Pharmacokinetic sampling at steady state was performed once in each patient between days -1 and +5 while on intravenous therapy and then repeated once between days 5 and 14 posttransplant after oral administration. There were no differences in total or unbound MPA 24 hour cumulative area under the curve (AUC), concentration at steady state (Css) or troughs between the two dosing regimens. Total MPA 24 hour AUC (median, [range]) exposures were not different between intravenous 1 gm every 8 hours (53.59 [22.86–101.99] mcg*hr/mL) and intravenous 1.5 gm every 12 hours (60.90 [35.89–127.24] mcg*hr/mL) regimen (p=0.34). Unbound MPA 24 hour AUC exposures were also not different between the intravenous 1 gm every 8 hours (0.942 [0.389–1.722] mcg*hr/mL) and intravenous 1.5 gm every 12 hours (1.081 [0.610–2.194] mcg*hr/mL)(p=0.25). Following oral therapy, total and unbound MPA 24 hour AUC exposures after 1 gm every 8 hours and 1.5 gm every 12 hours were also not different (p≥0.43). Total MPA Css after intravenous 1 gm every 8 hours, oral 1 gm every 8 hours, intravenous 1.5 gm every 12 hours, oral 1.5 gm every 12 hours were 2.23 [0.95–4.25], 2.05 [1.32–3.24], 2.53 [1.46–5.24] and 2.35 [1.47–4.05] mcg/ml, respectively (p≥0.15). We previously found that an unbound 24 hour cumulative MPA AUC <0.600 mcg*hr/mL was associated with higher risk of acute GVHD. The 3 gm/day regimens achieved an unbound 24 hour cumulative AUC target >0.600 mcg*hr/mL in 87–100% of subjects. All patients with the every 8 hour dosing had neutrophil recovery (ANC >500 cells/uL x 3 consecutive days) at a median [range] of day 10 [6–38] as compared to day 12 [0–31] in those with every 12 hour dosing. Acute GVHD grades II–IV developed in 3 (20%) and 6 (40%) patients in the MMF every 8 hour and every 12 hour dosing cohorts, respectively. When compared to our historical controls, MPA exposure is higher with MMF 3 gm/day compared to 2 gm/day regardless of dosing schedule and achieves adequate exposure in most adult patients. In conclusion, MMF 3 g/day should be considered the standard starting dose for adult patients undergoing nonmyeloablative HCT.