title: Explaining variability in mycophenolic acid exposure to optimize mycophenolate mofetil dosing: a population pharmacokinetic meta-analysis of mycophenolic acid in renal transplant recipients.
abstract: Large between- and within-patient variability has been observed in the pharmacokinetics of mycophenolic acid (MPA). However, conflicting results exist about the influence of patient characteristics that explain the variability in MPA exposure. This population pharmacokinetic meta-analysis of MPA in renal transplant recipients was performed to explore whether race, renal function, albumin level, delayed graft function, diabetes, and co-medication are determinants of total MPA exposure. A total of 13,346 MPA concentration-time data points from 468 renal transplant patients who participated in six clinical studies were combined and analyzed retrospectively. Sampling occasions ranged from day 1 after transplantation to 10 yr after transplantation. Concentration-time data were analyzed with nonlinear mixed-effect modeling. Exposure to total MPA, as determined by MPA clearance, significantly increased with increasing renal function, albumin level, and hemoglobin as well as decreasing cyclosporine predose level (P<0.001). These variables could explain 18% of the between-patient and 38% of the within-patient variability in MPA exposure. Differences in MPA exposure between patients with or without delayed graft function or between patients of different races are likely to be caused by the effect of renal function on MPA exposure. Diabetes did not have an effect on MPA exposure. The clinical implication is that a change in renal function or albumin level provides an indication for therapeutic drug monitoring as MPA exposure may be altered. Patients in whom cyclosporine and mycophenolate mofetil are combined may need higher mycophenolate mofetil doses, especially during the early phase after transplantation than currently recommended for optimal MPA exposure.
authors.affiliation: Department of Hospital Pharmacy, Erasmus MC, Rotterdam, The Netherlands. r.vanhest@erasmusmc.nl
authors.forename: Reinier M
authors.initials: RM
authors.lastname: van Hest
authors.forename: Ron A A
authors.initials: RA
authors.lastname: Mathot
authors.forename: Mark D
authors.initials: MD
authors.lastname: Pescovitz
authors.forename: Robert
authors.initials: R
authors.lastname: Gordon
authors.forename: Richard D
authors.initials: RD
authors.lastname: Mamelok
authors.forename: Teun
authors.initials: T
authors.lastname: van Gelder
mesh_terms: D000328:Adult; D000368:Aged; D019540:Area Under Curve; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006084:Graft Rejection / Q000517:prevention & control*; D006085:Graft Survival / Q000187:drug effects; D006801:Humans; D007676:Kidney Failure, Chronic / Q000601:surgery; D016030:Kidney Transplantation / Q000009:adverse effects / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D011379:Prognosis; D016032:Randomized Controlled Trials as Topic; D012016:Reference Values; D012189:Retrospective Studies; D014181:Transplantation Immunology / Q000187:drug effects*
chemical_list: D009173:Mycophenolic Acid