title: Limited sampling strategies using Bayesian estimation or multilinear regression for cyclosporin AUC(0-12) monitoring in cardiac transplant recipients over the first year post-transplantation.
abstract: OBJECTIVE
  The aim of this study was to develop routinely applicable limited sampling strategies for assessing cyclosporin (CsA) AUC(0-12 h), and possibly other exposure indices such as AUC(0-4 h) and C(max), in heart transplant patients over the first year post-transplantation.
  
  
  METHODS
  First, the individual pharmacokinetics (PKs) of 14 adult heart-transplant patients receiving Neoral were assessed at three post-transplantation periods, at the end of the first week (W1), the third month (M3) and the first year (Y1). To fit blood concentrations, a PK model specially developed for oral CsA was applied. Second, two statistical methods were compared for AUC(0-12 h) estimation using a limited sampling strategy (maximum of three blood samples): multiple regression analysis (MR) and Bayesian estimation (BE).
  
  
  RESULTS
  No significant difference was observed between the individual PK parameters at M3 and Y1, so population modelling was performed taking as a whole the concentration data collected at M3 and Y1. On the contrary, a significant difference ( P<0.05) was found for the C2/dose ratio between W1 and M3 and between W1 and Y1 (mean+/-SD =5.47+/-2.33; 7.78+/-1.05; 6.98+/-2.17 ml(-1 )for W1, M3 and Y1, respectively). Also, C(max)/dose and A were found significantly lower at W1 than at M3 ( P<0.01 and P<0.005, respectively), while lambda(1) was significantly higher at W1 than at both M3 and Y1 ( P<0.01). Using three sampling times (t0 h, t1 h and t3 h), BE allowed an accurate prediction of AUC(0-12 h) (mean bias =3.06+/-12.16%; +1.50+/-1.61%; and -0.20+/-11.42% at W1, M3 and Y1, respectively), AUC(0-4 h )and C(max). MR led to satisfactory estimation of AUC(0-12 h) using only two blood samples collected 2 h and 6 h post-dose (R=0.956-0.993; bias =-5.22 to +4.41; precision =6.38 to 9.90%), but this method is unable to estimate any other exposure index and requires strict respect of sampling times, contrary to BE.
  
  
  CONCLUSIONS
  Neoral monitoring based on full or abbreviated AUC is possible using BE or MR in heart transplant patients over the first year post-transplantation. BE provides a good description of the individual PK profiles and thus might be useful not only in case of potential discrepancies between C2 and clinical findings, but also for clinical trials aimed at finding optimum PK monitoring in heart recipients.
authors.affiliation: Department of Pharmacology and Toxicology, University Hospital, 2 Avenue Martin Luther King, 87042, Limoges, France.
authors.forename: C
authors.initials: C
authors.lastname: Monchaud
authors.forename: A
authors.initials: A
authors.lastname: Rousseau
authors.forename: F
authors.initials: F
authors.lastname: Leger
authors.forename: O J
authors.initials: OJ
authors.lastname: David
authors.forename: J
authors.initials: J
authors.lastname: Debord
authors.forename: T
authors.initials: T
authors.lastname: Dantoine
authors.forename: P
authors.initials: P
authors.lastname: Marquet
mesh_terms: D019540:Area Under Curve; D001499:Bayes Theorem; D016572:Cyclosporine / Q000097:blood / Q000493:pharmacokinetics*; D016027:Heart Transplantation / Q000706:statistics & numerical data*; D006801:Humans; D007166:Immunosuppressive Agents / Q000097:blood / Q000493:pharmacokinetics*; D016014:Linear Models
chemical_list: D007166:Immunosuppressive Agents; D016572:Cyclosporine