Pharmacokinetics of intravenous mycophenolate mofetil after allogeneic blood stem cell transplantation.
BACKGROUND
Mycophenolate mofetil (MMF) has shown synergistic effects in combination 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 active metabolite mycophenolic acid (MPA) in recipients of allogeneic blood stem cell transplants after oral administration of MMF, we initiated a phase I/II study evaluating different dose levels of the intravenous (i.v.) formulation 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 patients at each dose level. Plasma concentrations of MPA and its metabolite mycophenolic acid glucuronide (MPAG) were measured by high-performance liquid chromatography (HPLC).


RESULTS
Mean trough blood levels of MPA ranged between 68.8 and 340 ng/mL with a median of 146.7 ng/mL. The mean MPA AUC0-12 h after first dose ranged between 19349+/-5087 ng * h/mL and 25705+/-3042 ng * h/mL and correlated with the dose level of MMF. The incidence of acute 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 levels of MPA in patients after BSCT were ten times lower than in healthy volunteers. The toxicity induced by the conditioning therapy seems to negatively influence the pharmacokinetic behavior of MMF, MPA and MPAG.
Jenke
A
A
Medizinische Klinik und Poliklinik I, Universitätsklinikum Carl Gustav Carus, Fetscherstrasse 74, 01307 Dresden, Städtisches Klinikum Nord, Med. Klinik V, Flurstrasse 17, 90 419 Nürnberg, Germany.
Renner
U
U
Richte
M
M
Freiberg-Richter
J
J
Platzbecker
U
U
Helwig
A
A
Thiede
H M
HM
Schäfer-Eckart
K
K
Ehninger
G
G
Bornhäuser
M
M
D000328:Adult; D016572:Cyclosporine / Q000008:administration & dosage / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D005260:Female; D006086:Graft vs Host Disease / Q000517:prevention & control*; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000627:therapeutic use; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019172:Transplantation Conditioning
D007166:Immunosuppressive Agents; D016572:Cyclosporine; D009173:Mycophenolic Acid