Pharmacokinetic-Pharmacodynamic Modeling of the Electroencephalogram Effect of Imipenem in Healthy Rats

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Abstract
A pharmacokinetic-pharmacodynamic (PK-PD) modeling approach was developed to investigate the epileptogenic activity of imipenem in rats. Initially, animals received an intravenous infusion of imipenem at a rate of 2.65 mg min−1 for 30 min. Blood samples were collected for drug assay, and an electroencephalogram (EEG) was recorded during infusion and postinfusion. A dramatic delay was observed between concentrations of imipenem in serum and the EEG effect; this effect was accompanied by tremors and partial seizures. Indirect-effect models failed to describe these data, which were successfully fitted using an effect compartment model. The relationship between effect and concentration at the effect site was best described by a spline function. The elimination rate constant from the effect compartment was severalfold lower than that from the central compartment. The robustness of the model was then confirmed after administering the imipenem dose over 60 and 90 min. In conclusion, the successful PK-PD modeling of the imipenem EEG effect in rats constitutes a major improvement for better prediction of the epileptogenic risk associated with this antibiotic.