title: Pharmacokinetics, efficacy, and safety of mycophenolate mofetil in combination with standard-dose or reduced-dose tacrolimus in liver transplant recipients.
abstract: 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.
authors.affiliation: Department of Hepatobiliary Surgery and Visceral Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. nashan@uke.uni-hamburg.de
authors.forename: Björn
authors.initials: B
authors.lastname: Nashan
authors.forename: Faouzi
authors.initials: F
authors.lastname: Saliba
authors.forename: Francois
authors.initials: F
authors.lastname: Durand
authors.forename: Rafael
authors.initials: R
authors.lastname: Barcéna
authors.forename: Jose Ignacio
authors.initials: JI
authors.lastname: Herrero
authors.forename: Gilles
authors.initials: G
authors.lastname: Mentha
authors.forename: Peter
authors.initials: P
authors.lastname: Neuhaus
authors.forename: Matthew
authors.initials: M
authors.lastname: Bowles
authors.forename: David
authors.initials: D
authors.lastname: Patch
authors.forename: Angel
authors.initials: A
authors.lastname: Bernardos
authors.forename: Jürgen
authors.initials: J
authors.lastname: Klempnauer
authors.forename: René
authors.initials: R
authors.lastname: Bouw
authors.forename: Jane
authors.initials: J
authors.lastname: Ives
authors.forename: Richard
authors.initials: R
authors.lastname: Mamelok
authors.forename: Diane
authors.initials: D
authors.lastname: McKay
authors.forename: Matt
authors.initials: M
authors.lastname: Truman
authors.forename: Paul
authors.initials: P
authors.lastname: Marotta
mesh_terms: 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
chemical_list: D007166:Immunosuppressive Agents; D009173:Mycophenolic Acid; D016559:Tacrolimus