Pharmacokinetic-pharmacodynamic modeling of the electroencephalogram effect of norfloxacin in rats

Abstract

A previously developed pharmacokinetic-pharmacodynamic (PK-PD) modeling approach was used to investigate the epileptogenic activity of norfloxacin as a representative antibiotic with concentration-dependent antimicrobial activity. Rats received an intravenous infusion of norfloxacin at a rate of 5 mg kg of body weight(-1) min(-1) over 30 min. Blood samples were collected for drug assay, and an electroencephalogram (EEG) was recorded during infusion and postinfusion. An important delay was observed between concentrations of norfloxacin in plasma and the EEG effect. Indirect effect models failed to describe these data, which were successfully fitted by using an effect compartment model with a spline function to describe the relationship between effect and concentration at the effect site, as previously observed with imipenem. The robustness of the PK-PD model was then assessed by keeping the dose constant but increasing the duration of infusion to 120 and 240 min. Although this was accompanied by PK modifications, PD parameters did not vary significantly, and the PK-PD model still applied. In conclusion, the successful PK-PD modeling of the norfloxacin EEG effect in rats should be considered to predict and reduce the epileptogenic risk associated with this antibiotic as a representative fluoroquinolone (E. Fuseau and L. B. Sheiner, Clin. Pharmacol. Ther. 35:733-741, 1984).

FIG. 1.

(A) Total power of the EEG signal versus NOR concentrations in plasma in a representative rat. (B) Total power of the EEG signal versus NOR concentrations at the effect site for a representative rat. The solid line represents the best fit of the data according to the spline function model (equation 9).

FIG. 2.

Concentrations of NOR in plasma and EEG effect versus time for the same rat as in Fig. 1. Solid lines represent best PK and PK-PD fits. The parameter values of the PK model are as follows: V = 6240 ml kg⁻¹, k₁₀ = 0.032 min⁻¹, k₁₂ = 0.168 min⁻¹, and k₂₁ = 0.028 min⁻¹. The parameter values of the PK-PD model are as follows: P₀ = 0.496 mV², B = 0.023 mV² μM⁻¹, n = 7.4, and k_e0 = 0.009 min⁻¹.

FIG. 3.

Simulated EEG effect following NOR infusions at a dose of 150 mg kg⁻¹ for various durations (same rat and parameter values as in Fig. 1 and 2).