Authors: Djebli, Nassim¹; Rousseau, Annick; Hoizey, Guillaume²; Rerolle, Jean-Philippe³; Toupance, Olivier⁴; Yann Le Meur,³; Marquet, Pierre

Source: Clinical Pharmacokinetics, Volume 45, Number 11, 2006 , pp. 1135-1148(14)

Publisher: Adis International

Abstract:

Objectives: 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.

Conclusion: 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.

Keywords: Immunosuppressants; Pharmacokinetic modelling; Population pharmacokinetics; Renal transplant; Sirolimus

Document Type: Research article

Affiliations: 1: 1 Laboratory of Pharmacology, Faculty of Medicine, Limoges University, Limoges, France 2: 4 Department of Pharmacology Toxicology, University Hospital, Reims, France 3: 5 Department of Nephrology-Transplantation, University Hospital, Limoges, France 4: 6 Department of Nephrology and Hemodialysis, University Hospital, Reims, France

Publication date: 2006-01-01

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