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Antimicrobial Agents and Chemotherapy, January 2003, p. 138-143, Vol. 47, No. 1
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.1.138-143.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Modeling of Transfer Kinetics at the Serum-Cerebrospinal Fluid Barrier in Rabbits with Experimental Meningitis: Application to Grepafloxacin

Marc Pfister,1* Liping Zhang,1 Margareta Hammarlund-Udenaes,2 Lewis B. Sheiner,1 Cynthia M. Gerber,3 Martin G. Täuber,4 and Philippe Cottagnoud3

Department of Laboratory Medicine and Biopharmaceutical Sciences, University of California, San Francisco, California,1 Department of Medicine,3 Institute of Microbiology and Infectious Diseases, Inselspital, University of Berne, Berne, Switzerland,4 Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy, University of Uppsala, Uppsala, Sweden2

Received 11 June 2001/ Returned for modification 26 February 2002/ Accepted 24 September 2002

The goals of the present study were to model the population kinetics of in vivo influx and efflux processes of grepafloxacin at the serum-cerebrospinal fluid (CSF) barrier and to propose a simulation-based approach to optimize the design of dose-finding trials in the meningitis rabbit model. Twenty-nine rabbits with pneumococcal meningitis receiving grepafloxacin at 15 mg/kg of body weight (intravenous administration at 0 h), 30 mg/kg (at 0 h), or 50 mg/kg twice (at 0 and 4 h) were studied. A three-compartment population pharmacokinetic model was fit to the data with the program NONMEM (Nonlinear Mixed Effects Modeling). Passive diffusion clearance (CLdiff) and active efflux clearance (CLactive) are transfer kinetic modeling parameters. Influx clearance is assumed to be equal to CLdiff, and efflux clearance is the sum of CLdiff, CLactive, and bulk flow clearance (CLbulk). The average influx clearance for the population was 0.0055 ml/min (interindividual variability, 17%). Passive diffusion clearance was greater in rabbits receiving grepafloxacin at 15 mg/kg than in those treated with higher doses (0.0088 versus 0.0034 ml/min). Assuming a CLbulk of 0.01 ml/min, CLactive was estimated to be 0.017 ml/min (11%), and clearance by total efflux was estimated to be 0.032 ml/min. The population kinetic model allows not only to quantify in vivo efflux and influx mechanisms at the serum-CSF barrier but also to analyze the effects of different dose regimens on transfer kinetic parameters in the rabbit meningitis model. The modeling-based approach also provides a tool for the simulation and prediction of various outcomes in which researchers might be interested, which is of great potential in designing dose-finding trials.

* Corresponding author. Mailing address: Box 0626, UCSF, 521 Parnassus Ave., San Francisco, CA 94143-0626. Phone: (415) 502-1989. Fax: (415) 476-2796. E-mail: marc@c255.ucsf.edu.

Antimicrobial Agents and Chemotherapy, January 2003, p. 138-143, Vol. 47, No. 1
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.1.138-143.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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