Pharmacokinetics of intravenous mycophenolate mofetil after allogeneic blood stem cell transplantation

Background. Mycophenolate mofetil (MMF) has shown synergistic effects in co mbination with cyclosporin A (CsA) in prevention of acute graft versus host disease (GVHD) after allogeneic blood stem cell transplantation (BSCT) in preclinical animal models. After having measured low plasma levels of the a ctive metabolite mycophenolic acid (MPA) in recipients of allogeneic blood stem cell transplants after oral administration of MMF, we initiated a phas e I/II study evaluating different dose levels of the intravenous (i.v.) for mulation together with standard dose CsA. Methods. A total of 15 patients received i.v. MMF in two split doses for 21 d after allogeneic BSCT from related (n = 9) and unrelated (n = 6) donors. Total daily doses of 25, 28, 31 and 34 mg/kg were investigated in 3-5 pati ents at each dose level. Plasma concentrations of MPA and its metabolite my cophenolic acid glucuronide (MPAG) were measured by high-performance liquid chromatography (HPLC). Results. Mean trough blood levels of MPA ranged bet ween 68.8 and 340 ng/mL with a median of 146.7 ng/mL. The mean MPA AUC(0-12 h) after first dose ranged between 19349 +/- 5087 ng*h/ml and 25705 +/- 30 42 ng*h/ml and correlated with the dose level of MMF. The incidence of acut e GVHD > grade I was 40%. No dose limiting toxicities were observed. Conclusions. The application of i.v. MMF is safe at a weight-adjusted dose between 25 and 34 mg/kg after allogeneic BSCT. The measured trough blood le vels of MPA in patients after BSCT were ten times lower than in healthy vol unteers. The toxicity induced by the conditioning therapy seems to negative ly influence the pharmacokinetic behavior of MMF, MPA and MPAG.