Sirolimus Population Pharmacokinetic/Pharmacogenetic Analysis and Bayesian Modelling in Kidney Transplant Recipients

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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 *l/*3 and *1/*1 genotypes). The standard errors of all the parameter estimates were 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.

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