title: Pharmacokinetic modelling and development of Bayesian estimators for therapeutic drug monitoring of mycophenolate mofetil in reduced-intensity haematopoietic stem cell transplantation.
abstract: BACKGROUND
  Mycophenolate mofetil, a prodrug of mycophenolic acid (MPA), is used during non-myeloablative and reduced-intensity conditioning haematopoetic stem cell transplantation (HCT) to improve engraftment and reduce graft-versus-host disease (GVHD). However, information about MPA pharmacokinetics is sparse in this context and its use is still empirical.
  
  
  OBJECTIVE
  To perform a pilot pharmacokinetic study and to develop maximum a posteriori Bayesian estimators (MAP-BEs) for the estimation of MPA exposure in HCT.
  
  
  METHODS
  Fourteen patients administered oral mycophenolate mofetil 15 g/kg three times daily were included. Two consecutive 8-hour pharmacokinetic profiles were performed on the same day, 3 days before and 4 days after the HCT. One 8-hour pharmacokinetic profile was performed on day 27 after transplantation. For these 8-hour pharmacokinetic profiles, blood samples were collected predose and 20, 40, 60, 90 minutes and 2, 4, 6 and 8 hours post-dose. Using the iterative two-stage (ITS) method, two different one-compartment open pharmacokinetic models with first-order elimination were developed to describe the data: one with two gamma laws and one with three gamma laws to describe the absorption phase. For each pharmacokinetic profile, the Akaike information criterion (AIC) was calculated to evaluate model fitting. On the basis of the population pharmacokinetic parameters, MAP-BEs were developed for the estimation of MPA pharmacokinetics and area under the plasma concentration-time curve (AUC) from 0 to 8 hours at the different studied periods using a limited-sampling strategy. These MAP-BEs were then validated using a data-splitting method.
  
  
  RESULTS
  The ITS approach allowed the development of MAP-BEs based either on 'double-gamma' or 'triple-gamma' models, the combination of which allowed correct estimation of MPA pharmacokinetics and AUC on the basis of a 20 minute-90 minute-240 minute sampling schedule. The mean bias of the Bayesian versus reference (trapezoidal) AUCs was <5% with <16% of the patients with absolute bias on AUC >20%. AIC was systematically calculated for the choice of the most appropriate model fitting the data.
  
  
  CONCLUSIONS
  Pharmacokinetic models and MAP-BEs for mycophenolate mofetil when administered to HCT patients have been developed. In the studied population, they allowed the estimation of MPA exposure based on three blood samples, which could be helpful in conducting clinical trials for the optimization of MPA in reduced-intensity HCT. However, prior studies will be needed to validate them in larger populations.
authors.affiliation: INSERM U850, Limoges, France.
authors.forename: Franck
authors.initials: F
authors.lastname: Saint-Marcoux
authors.forename: Bernard
authors.initials: B
authors.lastname: Royer
authors.forename: Jean
authors.initials: J
authors.lastname: Debord
authors.forename: Fabrice
authors.initials: F
authors.lastname: Larosa
authors.forename: Faezeh
authors.initials: F
authors.lastname: Legrand
authors.forename: Eric
authors.initials: E
authors.lastname: Deconinck
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Kantelip
authors.forename: Pierre
authors.initials: P
authors.lastname: Marquet
mesh_terms: D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000493:pharmacokinetics; D019540:Area Under Curve; D001499:Bayes Theorem; D016903:Drug Monitoring / Q000379:methods; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D006801:Humans; D008297:Male; D008875:Middle Aged; D008962:Models, Theoretical; D009173:Mycophenolic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D010599:Pharmacokinetics; D010865:Pilot Projects; D011355:Prodrugs / Q000493:pharmacokinetics; D055815:Young Adult
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D011355:Prodrugs; D009173:Mycophenolic Acid