title: Time-dependent clearance of mycophenolic acid in renal transplant recipients.
abstract: OBJECTIVE
  Pharmacokinetic studies of the immunosuppressive compound mycophenolic acid (MPA) have shown a structural decrease in clearance (CL) over time after renal transplantation. The aim of this study was to characterize the time-dependent CL of MPA by means of a population pharmacokinetic meta-analysis, and to test whether it can be described by covariate effects.
  
  
  METHODS
  One thousand eight hundred and ninety-four MPA concentration-time profiles from 468 renal transplant patients (range 1-9 profiles per patient) were analyzed retrospectively by nonlinear mixed effect modelling. Sampling occasions ranged from day 1-10 years after transplantation.
  
  
  RESULTS
  The pharmacokinetics of MPA were described by a two-compartment model with time-lagged first order absorption, and a first-order term for time-dependent CL. The model predicted the mean CL to decrease from 35 l h(-1) (CV = 44%) in the first week after transplantation to 17 l h(-1) (CV = 38%) after 6 months. In a covariate model without a term for time-dependent CL, changes during the first 6 months after transplantation in creatinine clearance from 19 to 71 ml min(-1), in albumin concentration from 35 to 40 g l(-1), in haemoglobin from 9.7 to 12 g dl(-1) and in cyclosporin predose concentration from 225 to 100 ng ml(-1) corresponded with a decrease of CL from 32 to 19 l h(-1). Creatinine clearance, albumin concentration, haemoglobin and cyclosporin predose concentration explained, respectively, 19%, 12%, 4% and 3% of the within-patient variability in MPA CL.
  
  
  CONCLUSIONS
  By monitoring creatinine clearance, albumin concentration, haemoglobin and cyclosporin predose concentration, changes in MPA exposure over time can be predicted. Such information can be used to optimize therapy with mycophenolate mofetil.
authors.affiliation: Department of Hospital Pharmacy, Erasmus Medical Center, Rotterdam, The Netherlands. r.vanhest@erasmusmc.nl
authors.forename: Reinier M
authors.initials: RM
authors.lastname: van Hest
authors.forename: Teun
authors.initials: T
authors.lastname: van Gelder
authors.forename: René
authors.initials: R
authors.lastname: Bouw
authors.forename: Timothy
authors.initials: T
authors.lastname: Goggin
authors.forename: Robert
authors.initials: R
authors.lastname: Gordon
authors.forename: Richard D
authors.initials: RD
authors.lastname: Mamelok
authors.forename: Ron A
authors.initials: RA
authors.lastname: Mathot
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D005260:Female; D006084:Graft Rejection; D006801:Humans; D007166:Immunosuppressive Agents / Q000097:blood / Q000493:pharmacokinetics*; D007668:Kidney / Q000378:metabolism; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009173:Mycophenolic Acid / Q000097:blood / Q000493:pharmacokinetics*; D013997:Time Factors
chemical_list: D007166:Immunosuppressive Agents; D009173:Mycophenolic Acid