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Antimicrobial Agents and Chemotherapy, June 2001, p. 1682-1687, Vol. 45, No. 6
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.6.1682-1687.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

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

Antoine Dupuis,1,2,dagger William Couet,1,* Joël Paquereau,3 Stanley Debarre,1 Agnès Portron,1 Candice Jamois,1 and Serge Bouquet1,2

Laboratoire de Biopharmacie, Faculté de Médecine & Pharmacie, 86005 Poitiers Cedex,1 Laboratoire de Physiologie, Faculté de Médecine & Pharmacie, Poitiers,3 and Laboratoire de Pharmacocinétique, CHU la Milétrie, 86021 Poitiers Cedex,2 France

Received 29 September 2000/Returned for modification 10 February 2001/Accepted 8 March 2001

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.

* Corresponding author. Mailing address: Laboratoire de Biopharmacie, Faculté de Médecine & Pharmacie, 34 rue du Jardin des Plantes, 86005 Poitiers Cedex, France. Phone: 33 5 49 45 43 79. Fax: 33 5 49 45 43 78. E-mail: william.couet{at}univ-poitiers.fr.

dagger Present address: Department of Pharmaceutics, University of Washington, Seattle, WA 98195.

Antimicrobial Agents and Chemotherapy, June 2001, p. 1682-1687, Vol. 45, No. 6
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.6.1682-1687.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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