title: Bayesian estimation of mycophenolate mofetil in lung transplantation, using a population pharmacokinetic model developed in kidney and lung transplant recipients.
abstract: OBJECTIVE
  The immunosuppressive drug mycophenolate mofetil is used to prevent rejection after organ transplantation. In kidney transplant recipients, it has been demonstrated that adjustment of the mycophenolate mofetil dose on the basis of the area under the concentration-time curve (AUC) of mycophenolic acid (MPA), the active moiety of mycophenolate mofetil, improves the clinical outcome. Because of the high risks of rejections and infections in lung transplant recipients, therapeutic drug monitoring of the MPA AUC might be even more useful in these patients. The aims of this study were to characterize the pharmacokinetics of MPA in lung and kidney transplant recipients, describe the differences between the two populations and develop a Bayesian estimator of the MPA AUC in lung transplant recipients.
  
  
  METHODS
  In total, 460 MPA concentration-time profiles from 41 lung transplant recipients and 116 kidney transplant recipients were included. Nonlinear mixed-effects modelling was used to develop a population pharmacokinetic model. Patients were divided into an index dataset and a validation dataset. The pharmacokinetic model derived from the index dataset was used to develop a Bayesian estimator, which was validated using the 35 lung transplant recipients' profiles from the validation dataset.
  
  
  RESULTS
  MPA pharmacokinetics were described using a two-compartment model with lag time, first-order absorption and first-order elimination. The influence of ciclosporin co-treatment and the changes over time post-transplantation were included in the model. Lung transplant recipients had, on average, a 53% slower absorption rate and 50% faster MPA apparent oral clearance than kidney transplant recipients (p < 0.001). In lung transplant recipients, the bioavailability was, on average, 31% lower in patients with cystic fibrosis than in patients without cystic fibrosis (p < 0.001). The Bayesian estimator developed using the population pharmacokinetic model--and taking into account ciclosporin co-treatment, cystic fibrosis and time post-transplantation, with concentrations measured at 0, 1 and 4 hours after mycophenolate mofetil dose administration--resulted in a non-significant bias and mean imprecision of 5.8 mg · h/L. This higher imprecision compared with those of similar estimators that have previously been developed in kidney transplantation might have been caused by the high MPA pharmacokinetic variability seen in the lung transplant recipients and by the fact that a large proportion of the patients did not receive ciclosporin, which reduces variability in the elimination phase of MPA by blocking its enterohepatic cycling.
  
  
  CONCLUSIONS
  Lung transplant recipients have a slower MPA absorption rate and faster apparent oral clearance than kidney transplant recipients, while cystic fibrosis results in lower MPA bioavailability. A Bayesian estimator using MPA concentration-time samples at 0, 1 and 4 hours post-dose had the best predictive performance.
authors: INSERM Unit 850, CHU Limoges, University of Limoges, Limoges, France.
authors: Brenda C M
authors: BC
authors: de Winter
authors: Caroline
authors: C
authors: Monchaud
authors: Aurélie
authors: A
authors: Prémaud
authors: Christophe
authors: C
authors: Pison
authors: Romain
authors: R
authors: Kessler
authors: Martine
authors: M
authors: Reynaud-Gaubert
authors: Claire
authors: C
authors: Dromer
authors: Marc
authors: M
authors: Stern
authors: Romain
authors: R
authors: Guillemain
authors: Christiane
authors: C
authors: Knoop
authors: Marc
authors: M
authors: Estenne
authors: Pierre
authors: P
authors: Marquet
authors: Annick
authors: A
authors: Rousseau
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D019540:Area Under Curve; D001499:Bayes Theorem; D001682:Biological Availability; D003550:Cystic Fibrosis / Q000378:metabolism*; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics*; D016030:Kidney Transplantation; D016040:Lung Transplantation; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009173:Mycophenolic Acid / Q000031:analogs & derivatives / Q000493:pharmacokinetics*; D015203:Reproducibility of Results; D055815:Young Adult
chemical_list: D007166:Immunosuppressive Agents; D009173:Mycophenolic Acid