Pharmacokinetics, efficacy, and safety of mycophenolate mofetil in combination with standard-dose or reduced-dose tacrolimus in liver transplant recipients.
The pharmacokinetics of mycophenolate mofetil (MMF) in liver transplant recipients may change because of pharmacokinetic interactions with coadministered immunosuppressants or because changes in the enterohepatic anatomy may affect biotransformation of MMF to mycophenolic acid (MPA) and enterohepatic recirculation of MPA through the hydrolysis of mycophenolate acid glucuronide to MPA in the gut. In the latter case, the choice of formulation (oral versus intravenous) could have important clinical implications. We randomized liver transplant patients (n = 60) to standard (10-15 ng/mL) or reduced (5-8 ng/mL) trough levels of tacrolimus plus intravenous MMF followed by oral MMF (1 g twice daily) with corticosteroids. Pharmacokinetic sampling was performed after the last intravenous MMF dose, after the first oral MMF dose, and at selected times over 52 weeks. The efficacy and safety of the 2 regimens were also assessed. Twenty-eight and 27 patients in the tacrolimus standard-dose and reduced-dose groups, respectively, were evaluated. No significant differences between the tacrolimus standard-dose and reduced-dose groups were seen in dose-normalized MPA values of the time to the maximum plasma concentration (1.25 versus 1.28 hours), the maximum plasma concentration (15.5 +/- 7.93 versus 13.6 +/- 7.03 microg/mL), or the area under the concentration-time curve from 0 to 12 hours (AUC(0-12); 53.0 +/- 20.6 versus 43.8 +/- 15.5 microg h/mL) at week 26 or at any other time point. No relationship was observed between the tacrolimus trough or AUC(0-12) and MPA AUC(0-12). Exposure to MPA after oral and intravenous administration was similar. Safety and efficacy were similar in the two treatment groups. In conclusion, exposure to MPA is not a function of exposure to tacrolimus. The similar safety and efficacy seen with MMF plus standard or reduced doses of tacrolimus suggest that MMF could be combined with reduced doses of tacrolimus.
Nashan
Björn
B
Department of Hepatobiliary Surgery and Visceral Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. nashan@uke.uni-hamburg.de
Saliba
Faouzi
F
Durand
Francois
F
Barcéna
Rafael
R
Herrero
Jose Ignacio
JI
Mentha
Gilles
G
Neuhaus
Peter
P
Bowles
Matthew
M
Patch
David
D
Bernardos
Angel
A
Klempnauer
Jürgen
J
Bouw
René
R
Ives
Jane
J
Mamelok
Richard
R
McKay
Diane
D
Truman
Matt
M
Marotta
Paul
P
D000284:Administration, Oral; D000328:Adult; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D007262:Infusions, Intravenous; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D016559:Tacrolimus / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D016896:Treatment Outcome
D007166:Immunosuppressive Agents; D009173:Mycophenolic Acid; D016559:Tacrolimus