Pharmacokinetic-pharmacodynamic modeling of the electroencephalogram effect of imipenem in healthy rats

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.

FIG. 1

Characteristic EEG changes induced by imipenem infusion (80 mg over 30 min) in a typical rat (group I) before (a) and at the end of (b) infusion, at the maximum effect (c), and after return to the baseline (d).

FIG. 2

Observed total power of the EEG signal versus time and predicted values (solid line) according to the indirect-effect model with inhibition of the loss of effect, following imipenem infusion (80 mg over 30 min) in the same rat as in Fig. 1.

FIG. 3

Measured total power of the EEG signal versus imipenem concentrations in serum (A) and at the effect site (B), for the same rat as in Fig. 1. The solid line represents the best fit of the data according to the spline function model (equation 8).

FIG. 4

Concentrations of imipenem in serum and EEG effect versus time for the same rat as in Fig. 1. The broken line represents the best PK fit to the measured concentrations of imipenem in serum, with the following values for PK parameters: V = 254 ml kg⁻¹ and clearance = 14.0 ml min⁻¹ kg⁻¹. The solid line represents the best fit to the measured total power of the EEG signal effect, according to the effect compartment model, with the following values for PD parameters: P₀ = 0.17 mV², B = 0.0151, n = 8.1, and k_e0 = 0.0070 min⁻¹.

FIG. 5

Simulated EEG effect for the same rat as in Fig. 1 according to the effect compartment model following imipenem infusions. (A) The same dose (80 mg) administered for various durations, leads to changes in C_max but not in AUC. Lines correspond to infusions at 0 (bolus), 15, 30, 60, 90, 120, 150, and 180 min; solid lines represent experimental conditions used during this study. (B) Various rates (3.20, 2.85, 2.65, and 2.50 mg min⁻¹ for 20, 25, 30, and 35 min, respectively) lead to changes in doses (64, 71, 80, and 88 mg, respectively) and, therefore, AUC, but peak concentrations in serum (C_max = 437 μg ml⁻¹) do not change. The solid line corresponds to an experimental condition used in this study (30-min infusion).