title: Nonlinear relationship between mycophenolate mofetil dose and mycophenolic acid exposure: implications for therapeutic drug monitoring.
abstract: OBJECTIVE
  Mycophenolate mofetil (MMF) is an immunosuppressive drug used in renal transplant patients. Upon oral administration it is hydrolyzed to the active agent mycophenolic acid (MPA). In renal transplant recipients, MMF therapy is optimal when the area under the curve of MPA is 30 to 60 mg·h/L. When MMF doses are adjusted, a linear relationship between dose and MPA exposure is assumed. In this study, the linearity of MMF pharmacokinetics was investigated.
  
  
  METHODS
  MPA concentration-time profiles from renal transplant recipients cotreated with cyclosporine (n = 140) or tacrolimus (n = 101) were analyzed retrospectively using nonlinear mixed-effects modeling. The correlation between the MMF dose and the pharmacokinetics parameters was evaluated.
  
  
  RESULTS
  In the developed population pharmacokinetics model MPA clearance and the central volume of distribution were correlated with cyclosporine coadministration and time posttransplantation. The pharmacokinetics of MPA were not linear. Bioavailability decreased with increasing MMF doses. Compared with an MMF dose of 1000 mg (=100%), relative bioavailability was 123%, 111%, 94%, and 90% in patients receiving MMF doses of 250, 500, 1500, and 2000 mg in combination with cyclosporine (P < 0.001); respective values in tacrolimus-cotreated patients were 176%, 133%, 85%, and 76% (P < 0.001). Because of the decreasing relative bioavailability, MPA exposure will increase less than proportionally with increasing MMF doses.
  
  
  CONCLUSIONS
  MMF exhibits nonlinear pharmacokinetics. This should be taken into account when performing therapeutic drug monitoring.
authors.affiliation: Department of Hospital Pharmacy, Clinical Pharmacology Unit, Rotterdam, The Netherlands.
authors.forename: Brenda C M
authors.initials: BC
authors.lastname: de Winter
authors.forename: Ron A A
authors.initials: RA
authors.lastname: Mathot
authors.forename: Ferdi
authors.initials: F
authors.lastname: Sombogaard
authors.forename: Arnold G
authors.initials: AG
authors.lastname: Vulto
authors.forename: Teun
authors.initials: T
authors.lastname: van Gelder
mesh_terms: D000328:Adult; D000368:Aged; D001682:Biological Availability; D016572:Cyclosporine / Q000627:therapeutic use; D016903:Drug Monitoring; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D017711:Nonlinear Dynamics; D016032:Randomized Controlled Trials as Topic; D012189:Retrospective Studies; D016559:Tacrolimus / Q000627:therapeutic use; D055815:Young Adult
chemical_list: D007166:Immunosuppressive Agents; D016572:Cyclosporine; D009173:Mycophenolic Acid; D016559:Tacrolimus