Population pharmacokinetics of ertapenem in juvenile and old rats

Ertapenem is a parenteral broad-spectrum carbapenem active against Gram-negative pathogens, which has been approved for treatment of different infectious situations in adults and children. Favourable pharmacokinetics and pharmacodynamics have been established in young adults. In the elderly, dosing regimen adaptations are not recommended. Nevertheless, pharmacokinetic studies in paediatrics have not been published yet. The aim of this study was to document whether age influenced ertapenem disposition by comparing its pharmacokinetics in three groups of rats. Rats were separated into three groups: very young rats 21-day-old, 10-week-old and 7-month-old rats. A population pharmacokinetic model was built and evaluated, using the NONMEM software. Pharmacokinetic parameters, interindividual variability and residual variability were estimated. The final model was evaluated by a bootstrap procedure and visual predictive check. The ertapenem concentration-time data were best described by a one-compartment model with zero-order input and first-order elimination. Effect of very young and old ages was estimated on central volume and clearance. Model evaluation indicated that the model was robust and parameter estimates were accurate. Central volume was found to be dependent on age and increase with age. Although the dosing regimen was weight adjusted, clearance was found to depend not only on age but also on weight. This study clearly documents changes in ertapenem pharmacokinetics according to group of age. These results suggest that paediatric dosing regimen cannot be directly extrapolated from a pharmacokinetic model in young adults unless it took into account age-induced modifications.