BACKGROUND AND OBJECTIVES: Population pharmacokinetic studies of ciclosporin microemulsion are needed to identify the individual factors influencing ciclosporin pharmacokinetic variability in transplant patients and to design efficient tools for the accurate estimation of ciclosporin overall exposure (area under the plasma concentration-time curve from 0 to 12 hours [AUC12]). In the present retrospective study, a large database of heart, lung (with or without cystic fibrosis) and kidney (both adult and paediatric) transplant patients receiving ciclosporin microemulsion was analysed with the aims of (i) building a population pharmacokinetic model and finding the main covariates linked with ciclosporin microemulsion pharmacokinetic parameters; and (ii) developing a maximum a posteriori probability Bayesian estimator (MAP-BE) to estimate ciclosporin microemulsion pharmacokinetic parameters using a limited-sampling strategy. METHODS: 3,072 concentration data from 147 patients (i.e. 309 full pharmacokinetic profiles) were analysed using the nonlinear mixed-effects model program NONMEM. The influence of numerous covariates was tested, and the final model was validated by data splitting. For Bayesian estimation, the best limited-sampling strategy was determined based on the D-optimality criterion, and validation performed in an independent group of 60 patients. RESULTS: The pharmacokinetics of ciclosporin microemulsion were accurately described by a two-compartment model with Erlang distribution for the absorption process. The type of graft and post-transplantation period were identified as significant sources of variability of the absorption parameter. Both apparent volume of the central compartment after oral administration (V1/F) and apparent oral clearance (CL/F) increased with bodyweight. The best limited-sampling strategy for Bayesian estimation was 0 hour, 1 hour and 3 hour post-dose, providing accurate estimation of ciclosporin microemulsion AUC12 in all patients of the test group, with a mean bias of 2.0 +/- 10.5% (range: -19.1% to -21.4% and 95% CI -0.6, +4.7). CONCLUSION: Population pharmacokinetic analysis of ciclosporin microemulsion in allograft transplants resulted in the design of a new pharmacokinetic model for ciclosporin microemulsion, identification of significant covariates and the design of an accurate MAP-BE based on three blood concentrations and these covariates.
BACKGROUND AND OBJECTIVES: Population pharmacokinetic studies of ciclosporin microemulsion are needed to identify the individual factors influencing ciclosporin pharmacokinetic variability in transplant patients and to design efficient tools for the accurate estimation of ciclosporin overall exposure (area under the plasma concentration-time curve from 0 to 12 hours [AUC12]). In the present retrospective study, a large database of heart, lung (with or without cystic fibrosis) and kidney (both adult and paediatric) transplant patients receiving ciclosporin microemulsion was analysed with the aims of (i) building a population pharmacokinetic model and finding the main covariates linked with ciclosporin microemulsion pharmacokinetic parameters; and (ii) developing a maximum a posteriori probability Bayesian estimator (MAP-BE) to estimate ciclosporin microemulsion pharmacokinetic parameters using a limited-sampling strategy. METHODS: 3,072 concentration data from 147 patients (i.e. 309 full pharmacokinetic profiles) were analysed using the nonlinear mixed-effects model program NONMEM. The influence of numerous covariates was tested, and the final model was validated by data splitting. For Bayesian estimation, the best limited-sampling strategy was determined based on the D-optimality criterion, and validation performed in an independent group of 60 patients. RESULTS: The pharmacokinetics of ciclosporin microemulsion were accurately described by a two-compartment model with Erlang distribution for the absorption process. The type of graft and post-transplantation period were identified as significant sources of variability of the absorption parameter. Both apparent volume of the central compartment after oral administration (V1/F) and apparent oral clearance (CL/F) increased with bodyweight. The best limited-sampling strategy for Bayesian estimation was 0 hour, 1 hour and 3 hour post-dose, providing accurate estimation of ciclosporin microemulsion AUC12 in all patients of the test group, with a mean bias of 2.0 +/- 10.5% (range: -19.1% to -21.4% and 95% CI -0.6, +4.7). CONCLUSION: Population pharmacokinetic analysis of ciclosporin microemulsion in allograft transplants resulted in the design of a new pharmacokinetic model for ciclosporin microemulsion, identification of significant covariates and the design of an accurate MAP-BE based on three blood concentrations and these covariates.
Authors: J Debord; E Risco; M Harel; Y Le Meur; M Büchler; G Lachâtre; C Le Guellec; P Marquet Journal: Clin Pharmacokinet Date: 2001 Impact factor: 6.447
Authors: Dennis A Hesselink; Teun van Gelder; Ron H N van Schaik; Aggie H M M Balk; Ilse P van der Heiden; Thea van Dam; Marloes van der Werf; Willem Weimar; Ron A A Mathot Journal: Clin Pharmacol Ther Date: 2004-12 Impact factor: 6.875
Authors: Christiane Knoop; Ingrid Vervier; Philippe Thiry; Marc De Backer; John M Kovarik; Annick Rousseau; Pierre Marquet; Marc Estenne Journal: Transplantation Date: 2003-08-27 Impact factor: 4.939
Authors: Brian J Nankivell; Richard J Borrows; Caroline L-S Fung; Philip J O'Connell; Richard D M Allen; Jeremy R Chapman Journal: N Engl J Med Date: 2003-12-11 Impact factor: 91.245
Authors: Catherine M T Sherwin; Anna Carmela P Sagcal-Gironella; Tsuyoshi Fukuda; Hermine I Brunner; Alexander A Vinks Journal: Br J Clin Pharmacol Date: 2012-05 Impact factor: 4.335
Authors: Catherine M T Sherwin; Tsuyoshi Fukuda; Hermine I Brunner; Jens Goebel; Alexander A Vinks Journal: Clin Pharmacokinet Date: 2011-01 Impact factor: 6.447