title: Sirolimus population pharmacokinetic/pharmacogenetic analysis and bayesian modelling in kidney transplant recipients.
abstract: OBJECTIVE
  The objectives of the present study were: (i) to analyse the population pharmacokinetics of sirolimus in renal transplant recipients co-administered mycophenolate mofetil, but no calcineurin inhibitor over the first 3 months post-transplantation and study the influence of different potential covariates, including genetic polymorphisms of cytochrome P450 (CYP) metabolic enzymes and active transporters, on pharmacokinetic parameters; and (ii) to develop a Bayesian estimator able to reliably estimate the individual pharmacokinetic parameters and exposure indices in this population.
  
  
  METHODS
  Twenty-two adult renal transplant patients treated with sirolimus participated in this study. Ninety concentration-time profiles (938 sirolimus whole blood samples) were collected at days 7 and 14, and months 1 and 3 post-transplantation. The population pharmacokinetic study was conducted using the nonlinear mixed effects model software, NONMEM, and validated using both the bootstrap and the cross-validation approaches. Finally, a Bayesian estimator based on a limited sampling strategy was built using the post hoc option.
  
  
  RESULTS
  A two-compartment open model with first-order elimination and Erlang's distribution (to describe the absorption phase) best fitted the data. The mean pharmacokinetic parameter estimates were 5.25 h(-1), 218L and 292L for the transfer rate constant, the apparent volume of the central and peripheral compartments, respectively. The CYP3A5*1/*3 polymorphism significantly influenced the apparent oral clearance: mean oral clearance = 14.1 L/h for CYP3A5 non expressers (CYP3A5*3/*3 genotype) versus 28.3 L/h for CYP3A5 expressers (CYP3A5*1/*3 and *1/*1 genotypes). The standard errors of all the parameter estimates were <15%. Maximum a posteriori Bayesian forecasting allowed accurate prediction of sirolimus area under the concentration-time curve from 0 to 24 hours using a combination of only three sampling times (0, 1 and 3 hours post-dose), with a non-significant bias of -2.1% (range -22.2% to +25.9%), and a good precision (root mean square error = 10.3%). This combination is also easy to implement in clinical practice.
  
  
  CONCLUSIONS
  This study presents an accurate population pharmacokinetic model showing the significant influence of the CYP3A5*1/*3 polymorphism on sirolimus apparent oral clearance, and a Bayesian estimator accurately predicting sirolimus pharmacokinetics in patients co-administered mycophenolate mofetil, but no calcineurin inhibitor.
authors.affiliation: Laboratory of Pharmacology, Faculty of Medicine, Limoges University, Limoges, France.
authors.forename: Nassim
authors.initials: N
authors.lastname: Djebli
authors.forename: Annick
authors.initials: A
authors.lastname: Rousseau
authors.forename: Guillaume
authors.initials: G
authors.lastname: Hoizey
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Rerolle
authors.forename: Olivier
authors.initials: O
authors.lastname: Toupance
authors.forename: Yann
authors.initials: Y
authors.lastname: Le Meur
authors.forename: Pierre
authors.initials: P
authors.lastname: Marquet
mesh_terms: D000328:Adult; D000368:Aged; D019540:Area Under Curve; D001499:Bayes Theorem; D002986:Clinical Trials as Topic; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism; D004359:Drug Therapy, Combination; D005260:Female; D005838:Genotype; D006084:Graft Rejection / Q000517:prevention & control; D006801:Humans; D007166:Immunosuppressive Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D016030:Kidney Transplantation; D008099:Liver / Q000201:enzymology; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009173:Mycophenolic Acid / Q000031:analogs & derivatives / Q000627:therapeutic use; D011110:Polymorphism, Genetic; D011237:Predictive Value of Tests; D011446:Prospective Studies; D015203:Reproducibility of Results; D012189:Retrospective Studies; D020123:Sirolimus / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D013997:Time Factors
chemical_list: D007166:Immunosuppressive Agents; D003577:Cytochrome P-450 Enzyme System; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D009173:Mycophenolic Acid; D020123:Sirolimus