title: Predicting the usefulness of therapeutic drug monitoring of mycophenolic acid: a computer simulation.
abstract: The usefulness of therapeutic drug monitoring (TDM) of mycophenolate mofetil (MMF) was investigated with a computer simulation model. For a fixed-dose (FD) and a concentration-controlled (CC) MMF dosing regimen exposure to mycophenolic acid (MPA) was compared. A nonlinear mixed-effects model (NONMEM) for MPA based on extensive pharmacokinetic data from 140 renal transplant recipients who all used cyclosporine and corticosteroids as maintenance immunosuppressive therapy provided Bayesian estimates for MPA oral clearance on 9 occasions during the first 24 weeks after transplantation. In 45 of these patients, the estimates for MPA oral clearance were used to calculate values for the area under the curve (AUC) of MPA. In the CC group, MMF doses were adjusted based on the calculated AUC, targeting at an AUC level of 45 mg.h/L. In the FD group, MMF doses were fixed at 1000 mg. On day 7 after transplantation, significantly more AUC values were on target (AUC range 30-60 mg.h/L) in the CC group than in the FD group: 76% versus 13%, respectively, P < 0.001. To accomplish this, a doubling of MMF dose was necessary in more than half of the patients after the AUC assessment on day 3 after transplantation. Between-patient variability (BPV) in AUC (average CV% for all occasions) was reduced in the CC regimen: 23% versus 44% in the FD group. By using TDM, adequate MPA exposure appears to be obtained more rapidly, and BPV in exposure is reduced. To reach target AUC levels as soon as possible in this cyclosporine-treated population, it appears that larger MMF doses as currently recommended are necessary in the first month after transplantation.
authors.affiliation: Department of Hospital Pharmacy, Clinical Pharmacology Unit, Erasmus University Medical Center, PO Box 2040, 3000 CA Rotterdam, The Netherlands. r.vanhest@erasmusmc.nl
authors.forename: Reinier
authors.initials: R
authors.lastname: van Hest
authors.forename: Ron
authors.initials: R
authors.lastname: Mathot
authors.forename: Arnold
authors.initials: A
authors.lastname: Vulto
authors.forename: Willem
authors.initials: W
authors.lastname: Weimar
authors.forename: Teun
authors.initials: T
authors.lastname: van Gelder
mesh_terms: D000284:Administration, Oral; D019540:Area Under Curve; D001499:Bayes Theorem; D003198:Computer Simulation / Q000639:trends*; D004334:Drug Administration Schedule; D016903:Drug Monitoring / Q000379:methods*; D005260:Female; D005544:Forecasting; D006801:Humans; D016030:Kidney Transplantation / Q000502:physiology; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000276:immunology / Q000627:therapeutic use*; D010361:Patients; D016032:Randomized Controlled Trials as Topic; D012189:Retrospective Studies; D013997:Time Factors
chemical_list: D009173:Mycophenolic Acid