title: Bayesian forecasting of oral cyclosporin pharmacokinetics in stable lung transplant recipients with and without cystic fibrosis.
abstract: The aims of the current study were (1) to study Neoral pharmacokinetics (PK) in stable lung recipients with or without cystic fibrosis (CF), (2) to compare Neoral PK between these two groups, and (3) to design Bayesian estimators for PK forecasting and dose adjustment in these patients using a limited number of blood samples. The individual PK of 19 adult lung transplant recipients, 9 subjects with CF and 10 subjects without CF, were retrospectively studied. Three profiles obtained within 5 days were available for each patient. A PK model combining a gamma distribution to describe the absorption profile and a two-compartment model were applied. Different exposure indices were estimated using nonlinear regression and Bayesian estimation. The PK model developed reliably described the individual PK of Neoral in lung transplant patients with and without CF, and the values of the first and second half-lives were different in these two populations (lambda(1) = 4.14 +/- 3.01 vs. 2.16 +/- 1.75 h(-1); P < 0.01; lambda(2) = 0.36 +/- 0.11 vs. 0.49 +/- 0.12 h(-1); P < 0.01), while the mean absorption time and standard deviation of absorption time tended to be less in patients with cystic fibrosis (P < 0.1). Also, the patients with CF required higher doses than those without CF to achieve similar drug exposure. Consequently, population modeling was performed in CF and non-CF patients separately. Bayesian estimation allowed accurate prediction of AUC(0-12), AUC(0-4), C(max), and T(max) using three blood samples collected at T0h, T1h, and T3h in both groups. This study demonstrated the applicability and good performance of the PK model previously developed for oral cyclosporin and of the MAP Bayesian estimation of cyclosporin systemic exposure in CF and non-CF patients. Moreover, it is the first to propose a monitoring tool specifically designed for cyclosporin monitoring in patients with CF.
authors.affiliation: Department of Pharmacology and Toxicology, University Hospital, Limoges, France.
authors.forename: A
authors.initials: A
authors.lastname: Rousseau
authors.forename: C
authors.initials: C
authors.lastname: Monchaud
authors.forename: J
authors.initials: J
authors.lastname: Debord
authors.forename: I
authors.initials: I
authors.lastname: Vervier
authors.forename: M
authors.initials: M
authors.lastname: Estenne
authors.forename: P
authors.initials: P
authors.lastname: Thiry
authors.forename: P
authors.initials: P
authors.lastname: Marquet
mesh_terms: D000284:Administration, Oral; D000328:Adult; D019540:Area Under Curve; D001499:Bayes Theorem; D016572:Cyclosporine / Q000493:pharmacokinetics* / Q000627:therapeutic use; D003550:Cystic Fibrosis / Q000097:blood* / Q000188:drug therapy; D005260:Female; D006084:Graft Rejection / Q000097:blood* / Q000188:drug therapy; D006801:Humans; D016040:Lung Transplantation / Q000706:statistics & numerical data; D008297:Male; D008875:Middle Aged; D017711:Nonlinear Dynamics; D012189:Retrospective Studies; D018709:Statistics, Nonparametric
chemical_list: D016572:Cyclosporine